The last ten years have heralded remarkable progress in the understanding of the biogenesis of c-type cytochromes. The hallmark of c-type cytochrome synthesis is the covalent ligation of heme vinyl groups to two cysteinyl residues of the apocytochrome (at a CysXxxYyyCysHis signature motif). From genetic, genomic, and biochemical studies it is clear that three distinct systems have evolved in nature to assemble this ancient protein. In this review, common principles of assembly for all systems and the molecular mechanisms predicted for each system are summarized. Prokaryotes, plant mitochondria, and chloroplasts use either system I or II, which are each predicted to require a dedicated mechanism for heme delivery and apocytochrome thio-reduction. These two substrates are brought together at the site of cytochrome c function for covalent ligation. The third system has specifically evolved in the mitochondria of fungi, invertebrates, and vertebrates. For system III, a pivotal role is played by a single enzyme called cytochrome c heme lyase (CCHL) in the mitochondrial intermembrane space.