I never confronted my players with a 'boss' or 'Moriarty' as such. Sure, they faced adversaries but what they never faced was an individual out to get them specifically. They occasionally were targets for individuals and/or organizations, but no one was out to kill them simply because of who they were. It was more of a wrong place/wrong time sort of thing.
In one campaign the players did run afoul of Esperanzan military intelligence and that agency provided a continuing menace. However once the information the players had came out and once they were working for the Rift Republic, Esperanza backed off. Killing the players would no longer solve anything and revenge would just get Esperanza in more trouble.
Most of the sophonts my players went up against were antagonists. They were people on the other 'side' of business deals and other activities. Providing them with a continuing nemesis, someone who wanted them dead and buried over a long period of time, never really entered my mind.
This is not to say I didn't use long running NPCs to irritate my players however! Here are two they especially loved to hate:
Javier Blanco - There was a splendid private detective TV show in the 70s called The Rockford Files. James Garner starred in it and it was, for TV, one of the more realistic shows of the time. Garner as Rockford worked hard to make ends meet, worked low key cases, got into more trouble than a job was worth sometimes, and once even broke his hand punching a guy.
Before he became famous as Magnum PI, Tom Selleck guest starred in a few episodes as 'Lance White'. (Lance = Javelin = Javier and White = Blanco, get it?) Lance was a deliberately over-the-top heroic private detective straight out of a romance novel.
The writers had a great deal of fun inflicting White on Rockford. White was rich, good looking, perfect in every way. Women loved him, men admried him, strangers trusted him. He got straight answers from people who normally lie. When he told the bad guys to put down their guns and surrender they did just that instead of shooting him. His hair was never mussed, his clothes were perfect, and his teeth glittered white.
Lance White routinely did impossible things like shooting guns out of people's hands or knocking people out with karate chops. In one show, Rockford and another guy had spent hours searching a wooded area for something someone had thrown from a car without finding anything. White simply walked into the woods, bent over, picked up the item, and walked out.
You laughed out loud watching him and you were supposed to. Everyone on the show acted like dopes from some bad Hollywood movie around him. Only Rockford 'saw' how odd everything was.
I inflicted Javier Blanco on my players in the same manner the Rockford writers inflicted him on Jim Rockford. Blanco was the perfect tramp freighter captain and his ship, Tenalphi Heron, was a spotless problem free vessel. Blanco always beat them to lucrative speculative cargos. That free spending high roller travelled aboard Blanco's ship. Blanco always got the high priced charters too.
Every petty official, nasty broker, miserly shipper, and cranky noble who made life miserable for my players loved Javier Blanco. People couldn't wait to help him with any little task all he need to was ask. People even did things for him without Blanco asking.
Making matters worse, Blanco was a truly nice guy. He never lied and never knowing cheated anyone out of anything. If he found out he'd scooped you on a cargo he would give it back to you. Of course, his act of altruism would result in him getting an even better cargo later! When he got favorable treatment he made sure his friends recieved it too. The fuel boss will gladly bend over backwards to top off Blanco's tanks but the only reason he's doing the same for "you bums" is because Blanco asked him to.
Blanco brought the best out in people. They behaved better and more noble around him. His crew were heroes and his ship was involved in spectacular events. To everyone IMTU this was all normal. Like Rockford, only my players saw that it was weird and, like Rockford, it drove them crazy!
(I came up with Blanco well before Pratchett began writing the Discworld novels, but if you think of Captain Carrot Ironfoundersson you've got a good handle on Javier Blanco.)
Javier Blanco didn't show up in every session or even every other session. He did show up enough to make my players loathe him though. They'd scream in frustration after another "Blanco attack" and then thank me later for making the session so much fun. They loved to hate the guy and the fact that everyone else in the universe (inclusing the universe itself) loved Javier Blanco made their hate all the better.
Porky Grout - I lifted both the name and character straight from Hammett's Continental Op stories. I didn't even try to disguise him like I did with Lance White/Javier Blanco.
Porky is a stoolie, a rumor mill, a guy you go to for a 'read'. He knows everything you need to know about everyone and will rat anyone out for the price of a sandwich. He's middle aged, nondescript, addicted to a minor narcotic, and has the morals of a weasel. No wait, that's insulting to weasels.
Everything Porky knows, does, has, or guesses is for sale. He's no real threat to anyone because he's no good on the witness stand; no jury would believe him about anything. That more than anything has kept him alive. Another thing that has kept him alive is that he'll sell what he knows to anyone. Cop, criminal, whomever, it doesn't matter.
One thing to remember about Porky is that your question and the answer you recieved will be for sale immediately after you talk to him! Give him twenty for an address and he'll take the same from someone who wants to know what you wanted to know. Porky knows lots of secrets and keeps none.
Because he sells what he knows and hears, Porky will volunteer nothing. You want to know where the fellow you're looking for is living? He'll give you an address but he won't tell you about the five other armed men living there too unless you ask. He will tease you with bits trying to grind more money out of you, but he won't give away anything.
Hope all this crap is of some use.
Have fun,
Bill