Experimental evidence indicates that donor-specific antibodies targeting major histocompatibility complex classes I and II molecules can elicit the key features of transplant vasculopathy by acting on the graft vasculature in 3 ways: directly activating proliferative, prosurvival, and migratory signaling in the target endothelial and smooth muscle cells; increasing expression of mitogenic factors in vascular endothelial cells, creating a potential proliferative autocrine loop; and promoting recruitment of inflammatory cells that produce mitogenic factors and elicit chronic inflammation, proliferation, and fibrosis. Here, we review the experimental literature showing the complement and Fc-independent effects of major histocompatibility complex classes I and II antibodies on graft vascular cells that may directly contribute to the proliferative aspect of transplant vasculopathy.