BACKGROUND Cardiac allograft vasculopathy (CAV) is a major limitation to long-term survival after heart transplantation. Its peculiar pathophysiology involves multifactorial pathways including immune-mediated and metabolic risk factors, which are associated with the development of specific pathological lesions. The often diffuse and chronic nature of the disease reduces the effectiveness of revascularization procedures, and pharmacological prevention of the disease is the sole therapeutic approach with some proven efficacy. METHODS In this article, after briefly outlining the risk factors for CAV, the authors revise the potential pharmacological approaches that may reduce the burden of CAV. While several therapies have shown convincing efficacy in terms of CAV prevention diagnosed by coronary imaging, very few have been reported to improve prognosis with any meaningful level of evidence. CONCLUSIONS The authors believe that a customizable approach is necessary for clinical practice given the currently available evidence. Furthermore, it is important, in the future, to address the glaring therapeutic gap of an effective treatment against donor-specific antibodies, whose effect on endothelial injury is currently one of the major mechanisms of CAV development and for which no pharmacological treatment is currently available.