Poisons are a fantastic tool of any good GM. Instead of upping a monster’s combat stats to make it a nasty fight, just give it a poison (or disease) that it imparts upon anyone it hits. It’s a great leveler of the fighting grounds, and if the players know about the poisonous capabilities of your nasty critter, they will be hesitate to charge forth like a fool. Fore more details on poisons and how they can be used, check out Krystal’s words.
In most games I’ve been it it’s been a GM goof (or purposeful action) that kills the campaign. However, players can kill a campaign all on their own as well. This usually occurs in sandbox-style games, but can happen in a localized world of playstyle as well. Go see what Ameron has to say about the players derailing the GM’s carefully laid plans.
As a mortal creature, I can’t fathom having great powers or near-infinite time to plan out plots and ruses. I usually have to get my stuff together and get a project done in hours or days, not even weeks, months or years. I couldn’t imagine having decades, centuries or millennium to finish a task. Perhaps that tips over at roleplayingtips.com will help you out where I can’t.
Even the best laid mysteries with all of the hints and clues placed before the PCs can stall out. It could be some thick-headedness on the players’ parts, or just some bad dice rolls. Whatever throws you in that ditch, there are ways out of it. Go see what DNAPhil has to say on the matter. It’s good stuff.
I’ve ran a very few solo RPGs in the past because I’ve usually been blessed with good groups to game with. However, there are times when I’ve done it and it can be tricky. There just one character there to do everything necessary to move the plot forward and not to die against the Bad Things you throw at them. Johnn and Mike have some great advice on how to go about running a solo campaign. Go check them out.