Changes in the expression of photorespiratory genes induce and establish important phases of C-4 evolution.C-4 plants evolved independently more than 60 times from C-3 ancestors. C-4 photosynthesis is a complex trait and its evolution from the ancestral C-3 photosynthetic pathway involved the modification of the leaf anatomy and the leaf physiology accompanied by changes in the expression of thousands of genes. Under high temperature, high light, and the current CO2 concentration in the atmosphere, the C-4 pathway is more efficient than C-3 photosynthesis because it increases the CO2 concentration around the major CO2 fixating enzyme Rubisco. The oxygenase reaction and, accordingly, photorespiration are largely suppressed. In the present review we describe a scenario for C-4 evolution that not only includes the avoidance of photorespiration as the major driving force for C-4 evolution but also highlights the relevance of changes in the expression of photorespiratory genes in inducing and establishing important phases on the path from C-3 to C-4.