We examined the genes encoding the proteins that mediate the Ca-feedback regulatory system in vertebrate rod and cone phototransduction. These proteins comprise four families: recoverin/visinin, the guanylyl cyclase activating proteins (GCAPs), the guanylyl cyclases (GCs) and the sodium/ calcium-potassium exchangers (NCKXs). We identified a paralogon containing at least 36 phototransduction genes from at least fourteen families, including all four of the families involved in the Ca-feedback loop (recoverin/visinin, GCAPs, GCs and NCKXs). By combining analyses of gene synteny with analyses of the molecular phylogeny for each of these four families of genes for Ca-feedback regulation, we have established the likely pattern of gene duplications and losses underlying the expansion of isoforms, both before and during the two rounds of whole-genome duplication (2R WGD) that occurred in early vertebrate evolution. Furthermore, by combining our results with earlier evidence on the timing of duplication of the visual G-protein receptor kinase genes, we propose that specialization of proto-vertebrate photoreceptor cells for operation at high and low light intensities preceded the emergence of rhodopsin, which occurred during 2R WGD.