In kidney transplantation, it is well established that donor-specific antibodies can cause substantial graft injury. Hyperacute rejection, now virtually eliminated by routine pretransplant cytotoxic crossmatch testing, represents the prototype of humoral rejection. However, there is now increasing evidence that alloantibody-mediated immune reactions may also cause acute rejection. Acute humoral rejection, which is frequently associated with severe graft dysfunction and immunologic graft loss, represents a particular diagnostic and therapeutic challenge. Reliable detection of antibody-mediated graft injury is required to govern the application of antihumoral therapeutic strategies. This review focuses on new approaches in the diagnosis and treatment of acute humoral rejection. Special attention is given to a novel diagnostic marker, the complement split product C4d.