The ion calcium is a ubiquitous second messenger, present in all eukaryotic cells. It modulates a vast number of cellular events, such as cell division and differentiation, fertilization, cell volume, decodification of external stimuli. To process this variety of information, the cells display a number of calcium pools, which are capable of mobilization for signaling purposes. Here we review the calcium signaling on lizards red blood cells, an interesting model that has been receiving an increasing notice recently. These cells possess a complex machinery to regulate calcium, and display calcium responses to extracellular agonists. Interestingly, the pattern of calcium handling and response are divergent in different lizard families, which enforces the morphological data to their phylogenetic classification, and suggest the radiation of different calcium signaling models in lizards evolution.