Age-related macular degeneration (AMD) is the leading cause of vision loss in the US. It affects more than 9 million people and these numbers are likely to reach epidemic proportions in the coming decade. It is thought that the disease originates in a monolayer of pigmented epithelium cells located in the back of the eye - the retinal pigment epithelium (RPE). RPE performs multiple functions that are fundamentally important for the health and integrity of photoreceptors, including regulation of nutrient and metabolite flow, regeneration of visual pigment, and phagocytosis of shed photoreceptor outer segments. Consequently, RPE dysfunction or atrophy leads to photoreceptor cell death and vision loss, as seen in AMD patients. Genome-wide association studies have identified multiple (approximately 40) risk alleles associated with AMD and these risk-alleles affect different RPE signaling pathways whose dysregulation cause AMD progression. Thus, the AMD Integrative Biology Initiative seeks a more precise description of AMD disease pathobiology by using AMD genetic risk factors as sentinels for specific RPE signaling pathways and for changes in RPE physiology. We hope that this approach guides researchers to the development of personalized therapies for AMD.