The molecular entities present on a cell or organ transplant that trigger the innate immune response and link to the adaptive immune system are increasingly recognized as a key influence on early graft function and for determining the microenvironment that will guide longer-term graft outcomes. The 2014 Beaune Seminar in Transplant Research discussed the evidence for triggers, sensors, and modulators of innate and adaptive immunity in response to alloantigens, challenged the conventional view, developed novel hypotheses, and highlighted the potential for therapeutic manipulation of these responses.