Graft-versus-host disease (GVHD) is a serious complication of allogeneic hematopoietic cell transplantation (HCT) and this occurs as donor T lymphocytes, activated by recipient antigen presenting cells (APC), attack the host tissues or organs. This APC activation is a crucial initial step of influencing the outcome of GVHD and is mediated by innate immune signaling. Toll-like receptors (TLRs) and nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) are important components of innate immunity; both families of receptors are known for sensing various microbial ligands or danger signals. Signaling through TLRs/NLRs regulate activities of APCs, through phagocytosis, cytokine and chemokine release, delivery of APCs from peripheral tissues to draining lymph nodes, and antigen presentation. Several TLRs/NLRs have been identified and their ligands and signaling pathways have been described. Recent findings suggest a significant association of TLR/NLR polymorphisms with the increased risk for severe GVHD. Therefore, these TLR/NLR pathways likely contributing to immune response for GVHD may serve as novel therapeutic targets to facilitate allograft tolerance. This review summarizes the role of TLRs/NLRs innate immune receptors and signaling in GVHD pathophysiology.