Cyanobacteria, among Earth's oldest organisms, have evolved sophisticated biosynthetic pathways to produce a rich arsenal of bioactive natural products. In consequence, cyanobacterial secondary metabolites have been an incredibly fruitful source of lead compounds in drug discovery efforts. Investigations into the biochemistry responsible for the creation of these compounds, complemented by genome sequencing efforts, are revealing unique enzymatic mechanisms not described or rarely described elsewhere in the natural world. Herein, we discuss recent advances in understanding the biosynthesis of three cyanobacterial classes of natural product: mixed polyketide synthase/non ribosomal peptide synthetase (PKS/NRPS) metabolites, aromatic amino acid-derived alkaloids, and ribosomally encoded cyclic peptides. The unique biosynthetic mechanisms employed by cyanobacteria are inspiring new developments in heterologous gene expression and biotechnology.