The role of anti-HLA antibodies in solid organ rejection is well established and these antibodies are routinely monitored both in patients in the waiting list and in the post-transplant setting. More recently, the presence of other antibodies directed towards non-HLA antigens, or the so-called minor histocompatibility antigens, has drawn the attention of the transplant community; however, their possible involvement in the graft outcome remains uncertain. These antibodies have been described to possibly have a role in rejection and allograft failure. This review focuses on the most studied non-HLA antibodies and their association with different clinical outcomes considered in solid organ transplantation with the aim of clarifying their clinical implication and potential relevance for routine testing.