Disorders of lipid metabolism are strongly associated with cardiovascular disease. Recently, there has been significant focus on how tissues process lipid deposits. Impaired cholesterol efflux has been shown to be crucial in mediating lipid deposition in atherosclerosis. The inability of macrophages to effectively efflux cholesterol from tissues initiates inflammation, plaque neovascularization, and subsequent rupture. Recent studies suggest that inability to effectively efflux cholesterol from tissues may have global implications far beyond atherosclerosis, extending to the pathophysiology of unrelated diseases. We examine the unifying mechanisms by which impaired cholesterol efflux facilitates tissue-specific inflammation and disease progression in age-related macular degeneration (AMD), a blinding eye disease, and in atherosclerosis, a disease associated with significant cardiovascular morbidity.