Age-related macular degeneration (AMD) is a complex disease with both environmental and genetic factors influencing disease risk. Genome-wide case-control association studies, candidate gene analyses, and epidemiological studies reinforced the notion that AMD is predominantly a disease of an impaired complement system and an altered high-density lipoprotein (HDL) metabolism. Recent reports demonstrated the pleiotropic role of the complement system and HDL in complex diseases such as cardiovascular disease, autoimmune disorders, cancer, and Alzheimer’s disease. In light of these findings, we explore current evidence for a shared genetic and environmental risk of AMD and unrelated complex diseases based on epidemiological studies. Shared risk factors may indicate common pathways in disease pathology and thus may have implications for novel treatment options of AMD pathology.