This account summarizes the results of studies carried out by the authors during the last 10 years aimed at expanding the utility of the venerable Passerini and Ugi reactions. Particular emphasis is given to efforts that focus oil coupling these processes with post-condensation, intramolecular, aliphatic nucleophilic substitution and acyl nucleophilic substitution reactions. The methodologies developed in these investigations serve as the basis for short sequences for the preparation of a diverse number of interesting drug-like structures.