Acute graft‐versus‐host disease (aGVHD) is a major life‐threatening complication of allogeneic haematopoietic cell transplantation (allo‐HCT). Here we discuss the aGVHD pathophysiology initiated by multiple signals that cause alloreactive T‐cell activation. The outcome of such donor T‐cell activation is influenced by T‐cell receptor‐signal strength, anatomical location, co‐stimulatory/co‐inhibitory signals and differentiation stage (naive, effector/memory) of T‐cells. Additionally, cross‐priming of T cells to antigens expressed by pathogens can contribute to aGVHD‐mediated tissue injury. In addition to the properties of donor T‐cell activation, highly specialized tissue resident cell types, such as innate lymphoid cells, antigen‐presenting cells, immune regulatory cells and various intestinal cell populations are critically involved in aGVHD pathogenesis. The role of the thymus and secondary lymphoid tissue injury, non‐haematopoietic cells, intestinal microflora, cytokines, chemokines, microRNAs, metabolites and kinases in aGVHD pathophysiology will be highlighted. Acute GVHD pathogenic mechanisms will be connected to novel therapeutic approaches under development for, and tested in, the clinic.