The human leukocyte antigen (HLA) is a complex genetic system that encodes proteins which predominantly regulate immune/inflammatory processes. It can be involved in a variety of immuno-inflammatory disorders ranging from infections to autoimmunity and cancers. The HLA system is also suggested to be involved in neurodevelopment and neuroplasticity, especially through microglia regulation and synaptic pruning. Consequently, this highly polymorphic gene region has recently emerged as a major player in the etiology of several major psychiatric disorders, such as schizophrenia, autism spectrum disorder and bipolar disorder and with less evidence for major depressive disorders and attention deficit hyperactivity disorder. We thus review here the role of HLA genes in particular subgroups of psychiatric disorders and foresee their potential implication in future research. In particular, given the prominent role that the HLA system plays in the regulation of viral infection, this review is particularly timely in the context of the Covid-19 pandemic.