Gen I - Never played Gen.I, but in FRLG Sabrina definitely gave me the most grief.
Gen II - It's between Whitney and Clair. Eff that Miltank.
Gen III - When I lack a fire/fighting type, it's Wattson. Otherwise... probably Norman.
Gen IV - I might let Volkner take this one. None of them really gave me trouble.
The games seem to be getting easier, though that may be because I have more personal experience under my belt nowadays.