T-cells play a critical role in protective immunity, with their broad receptor repertoire capable of engaging diverse foreign pMHC landscapes. While the versatility and specificity of this MHC-restricted response is the hallmark of adaptive immunity, unwanted TCR interactions can profoundly effect the health of the host leading for instance to allograft rejection or autoimmunity. In allogeneic transplantation, such adverse reactions can occur by an indirect pathway when the TCR interacts with self-MHC molecules presenting allogeneic MHC derived peptides. Direct T-cell alloreactivity involves recognition of the allogeneic molecule itself either through molecular mimicry or by novel pMHC binding modes. By contrast, auto-reactive TCRs are considered to interact in a manner distinct from cognate pMHC interactions. Here we review recent advances in the field, focusing on structural data pertaining to alloreactivity and auto-reactivity and discuss implications for T-cell mediated transplant rejection and autoimmune disorders.