Heterogeneous catalysts streamline industrial processes due to high stability and ease of separation. Efforts toward predictive catalytic activity and rational design of next-generation systems are impeded by structural ambiguity stemming from the presence of multiple irregular active sites within a catalyst. The uniformity of metal–organic frameworks (MOFs) provides a platform on which to develop single site catalysts in order to delineate atomically precise design rules. In this critical review, we highlight the development and progress of MOF-based single site catalysts and provide an outlook for further advancement of the field.