Graft versus host disease (GVHD) remains the major cause of morbidity and nonrelapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (HSCT). Although the understanding of its biological basis is continuously improving and candidate target pathways therefore increasingly emerge, severe, steroid-refractory GVHD remains an unsolved issue with a rather poor prognosis in clinical practice thus far. With the exception of the Janus kinase (JAK) 1/2 inhibitor, ruxolitinib, which has demonstrated considerable effectiveness in steroid-refractory GVHD in a multicenter survey, few advances have been recognized in this field during recent years. Therefore, developments toward better, more individualized GVHD prophylaxis are needed. This, however, requires a more precise knowledge of risk factors for severe GVHD. One such emerging risk factor is the homozygosity for HLA-C group 1 killer cell immunoglobulin-like receptor (KIR) ligands. In addition, ongoing investigation into the predictive value of immunogenetic polymorphisms and post-transplant biomarkers will contribute to individually designed and adaptable GVHD management in the future, hopefully relying mainly on prophylactic and pre-emptive measures.