Age-related macular degeneration (AMD), affecting circa 200 million people worldwide, is a debilitating disease leading to visual loss in the elderly population. The main risk for AMD is advanced age. Genetic predisposition as well as modern lifestyle habits, such as smoking or unhealthy diets, increase this risk. On the molecular level, these risks convert into complex systemic changes at the interface of the choriocapillaris, Bruch's membrane, RPE, and neuroretina, affecting the functional integrity and survival of RPE and photoreceptors cells. To date, therapeutic options for AMD patients are limited. Pathway identification and a detailed understanding of the molecular mechanisms driving AMD are prerequisites to defining potential novel druggable targets. This review aims to give a short overview of the known cell signaling pathways focusing on RPE cells in response to stress conditions occurring in AMD.