Although 85,000 heart transplantations have been performed worldwide, coronary allograft vasculopathy (CAV), which is a phenomenon of chronic rejection, is still a serious problem. Because CAV involves all the allograft arteries, angioplasty, stenting or bypass grafting are not practical treatment options. Therefore, CAV is the biggest long-term limitation in cardiac allograft recipients. Although the cause of CAV is mostly immunologic, nonimmune pathways also contribute to its development. Several cytokines, chemokines and adhesion molecules play a critical role in the process. Cell adhesion, migration and proliferation of bone marrow progenitor and and other cells are involved in its development. Although there is not an established clinical strategy for preventing or treating CAV, recent investigations have provided some promising methodologies. Progress in DNA technology, such as antisense oligodeoxynucleotides (ODNs) to regulate the transcription of disease-related genes, has an important role in its therapeutic applications. Antisense ODN transfection preventing CAV in experimental cardiac allografts has been reported for the first time. The ODN strategy has not only been useful in the experimental studies, but is also a novel clinical strategy for gene therapy. The pathological and immunological characteristics of CAV and some promising methodologies for prevention of the disease are reviewed. (Circ J 2010; 74: 233-239)