Experimental clinical evidence has highlighted the importance of early posttransplantation events in determining allograft survival. Graft inflammation is initiated by activation of cellular and humoral components of innate immunity in an antigen-independent manner. Subsequently, the alloreactive response is driven by donor-specific T-cell–dependent adaptive immunity. A positive cross-talk between innate and adaptive responses governs the magnitude of the host-versus-graft response. This article reviews recent studies on the cellular and molecular pathways through which innate immunity may trigger allograft rejection.