This review focuses on nontemplate-dependent polymerases that use water-soluble substrates and convert them into water-insoluble polymers that form granules or inclusions within the cell. The initial part of the review summarizes briefly the current knowledge of polymer formation catalyzed by starch and glycogen synthases, polyphosphate kinase (a polymerase), cyanophycin synthetases, and rubber synthases. Specifically, our current understanding of their mechanisms of initiation, elongation (including granule formation), termination, remodeling, and polymer reutilization will be presented. General underlying principles that govern these types of polymerization reactions will be enumerated as a paradigm for all nontemplate-dependent polymerizations. The bulk of the review then focuses on polyhydroxyalkanoate (PHA) synthases that generate polyoxoesters. These enzymes are of interest as they generate biodegradable polymers. Our current knowledge of PHA production and utilization in vitro and in vivo as well as the contribution of many proteins to these processes will be reviewed.