Cyclobutanones hold a privileged role in enantioselective desymmetrization because their inherent ring strain allows for a variety of unusual reactions to occur. Current strategies include α-functionalization, rearrangement, and C-C bond activation to directly convert cyclobutanones into a wide range of enantiomerically enriched compounds, including many biologically significant scaffolds. This Minireview provides an overview of state-of-the-art methods that generate complexity from prochiral cyclobutanones in a single operation.