The domestobot mission irritated me at first, but I got the hang of it the 3rd time. I have 3 hardest missions, they are:
Unfriendly Competition
Light My Pyre
Kill Phil Part 2
Unfriendly Competition is when you have to kill a load of women in bikinis, who are all shooting at you at once. It's very frustrating trying to eliminate all of them, especially when some of them are in the pool just ahead of your starting point. After that, you have to chase a drug dealer on a shitty quad bike while a woman is on the back of his quad, shooting at you with an M4 (or something similar to that).
Light My Pyre is when Lance is on a motorbike chasing down Mendez's goons who stole his Infernus. You start off with no cars around you, so you have to quickly find one. Almost every time I did the mission, I jacked a Perrenial, which is so slow and has almost no protection from bullets. You have to stop the cars attacking Lance, who has a health bar. It repeatedly goes down so you have to distract the cars somehow. So I decided to ram the car to stop it shooting at Lance, it then shoots my car and blows it up within 8 or so seconds.
Kill Phil Part 2 is my worst mission. You have to kill wave after wave of gang members who are after Phil Collins. What's worse, you're in a huge stadium and you have to run to 4 different sections to kill the goons encamped there. That wasn't a problem for me, but if your Vic hasn't walked a lot and has next to no stamina, it's near impossible to get to each section on time. Add to that once you've cleared the 4 sections of goons, you have to run to the basement and kill 10 or more heavily armoured guards with assault rifles, and it makes a very irritating mission.