First time playing We Don't Go To Ravenholm, running out of ammo and with no handy lethal objects nearby, and hearing the roar of a Black Head Crab Zombie...
Also, playing the finale of Blood Harvest on L4D for the first time, and realising there are no molotovs or pipe bombs lying around...
Speaking of L4D, the other day I was playing Dead Air on single player (after getting frustrated with my slow connection trying to play Versus). After lowering the crate to progress, having survived all the waves of Infected, I climbed up the ladder... to come face to face with a Tank, without any warning sting of music. Right at the top of the ladder.
Needless to say, I back-pedalled very rapidly.