Safe vs. Unsafe
Baserunners are notorious for leading off from a base in hopes of getting an early start at advancing to the next base. If a baserunner is overconfident in his leadoff, he may be susceptible to a pickoff.
1st Base Pickoffs
Pickoffs most often occur at first base. Before a pitch, the pitcher will quickly throw the baseball to the first baseman, who tries to tag out the baserunner with the baseball. If the first baseman tags the runner before the runner touches first base, the runner is out and the pickoff is successful.
Hidden Ball Trick
Sometimes, in order to pick runners off, infielders will deceive runners. They will pretend that they do not have the baseball -- by hiding it, pretending to throw it, etc. -- then quickly tag the oblivious runner off when he steps off the base. This is a pretty rare feat, and not something that is commonly practiced.