In vitro selection can be used to generate nucleic acid ligands (aptamers) to target molecules ranging in size and structure from cations to cells. However, the selection process is repetitive and time-consuming. We have automated a protocol for in vitro selection using an augmented Beckman Biomek 2000 pipetting robot. The automated selection procedure requires the integration of four devices and the optimization of four molecular biology methods, and is one of the most complex automated protocols attempted to date. Initial attempts at selection yielded robust replication parasites, but optimization of the automated selection procedure suppressed the emergence of these parasites and led to the selection of true nucleic acid ligands. Automated selection can now be used to generate nucleic acid aptamers in days rather than weeks or months.