Over the past 40 years, cardiac transplantation has evolved as the single best long-term option for eligible candidates with end-stage heart failure. Approximately 2000 transplants are performed annually in the United States, and with the institution of calcineurin-based immunotherapy, surveillance biopsies, and programmatic-based patient care, life expectancy at 1 and 12 years is 85% and 50%, respectively. Cardiac allograft vasculopathy (CAV) is the number one cause of death after the first year of transplantation. The incidence of CAV remains as high as 50% at 5 years, with life expectancy significantly abbreviated once it is recognized. Although current immunotherapy has reduced the likelihood of cellular rejection, it has not impacted CAV substantially. Better treatment of established risk factors and the advent of newer antiproliferative immunotherapy may hold promise in treating CAV. However, future therapies must address the multitude of mechanisms underlying CAV. This manuscript reviews the pathophysiology, clinical manifestations, screening, and diagnostic strategies for cardiac allograft vasculopathy while emphasizing current treatment paradigms designed to stave off or retard the progression of CAV.