The discovery of disc protein renewal in rod outer segments, in 1960s, was followed by the observation that old discs were ingested by the retinal pigment epithelium. This process occurs in both rods and cones and is crucial for their survival. Photoreceptors completely degenerate in the Royal College of Surgeons mutant rat, whose pigment epithelium cannot ingest old discs. The complete renewal process includes the following sequential steps involving both photoreceptor and pigment epithelium activity: new disc assembly and old disc shedding by photoreceptor cells; recognition and binding to pigment epithelium membranes; then ingestion, digestion, and segregation of residual bodies in pigment epithelium cytoplasm. Regulating factors are involved at each step. While disc assembly is mostly genetically controlled, disc shedding and the subsequent pigment epithelium phagocytosis appear regulated by environmental factors (light and temperature). Disc shedding is rhythmically controlled by an eye intrinsic circadian oscillator using endogenous dopamine and melatonin as light and dark signal, respectively. Of special interest is the regulation of phagocytosis by multiple receptors, including specific phagocytosis receptors and receptors for neuroactive substances released from the neuroretina. The candidates for phagocytosis receptors are presented, but it is acknowledged that they are not completely known. The main neuromodulators are adenosine, dopamine, glutamate, serotonin, and melatonin. Although the transduction mechanisms are not fully understood, attention was brought to cyclic AMP, phosphoinositides, and calcium. The chapter points to the multiplicity of regulating factors and the complexity of their intermingling modes of action. Promising areas for future research still exist in this field.