In solid organ transplantation (SOT), the clinical relevance of donor-specific antibodies (DSA) directed at anti-HLA-A, -B, -DR and -DQ antigens is largely recognized while it is still a matter of debate for DSA directed at HLA-C. In this review, we summarize the peculiarities of HLA-C among class I HLA antigens as well as their immunogenicity, which underlie the clinical relevance of HLA-C locus and anti-HLA-C DSA in SOT. Many factors, both intrinsic and extrinsic to the HLA-C gene and HLA-C protein, explain its lower expression in comparison with HLA-A and -B. This lower expression can explain the apparent lower immunogenicity of HLA-C leading to a lower prevalence and strength of anti-HLA-C antibodies. Nevertheless, HLA-C antigens are truly immunogenic and preformed anti-HLA-C DSA are clinically relevant. Indeed, anti-HLA-C DSA are able to bind donor cells and to activate the complement pathway both ex vivo and in vivo. In line with this, numerous clinical studies now show that preformed DSA directed at native HLA-C molecules induce poorer graft outcomes. We then plead for the inclusion of HLA-C in all transplant allocation systems and we propose a strategy to cope with anti-HLA-C DSA in SOT. Beyond SOT, anti-HLA-C antibodies generate a growing interest in the allo-HCT, transfusion and obstetrics fields, while new concepts such as the role of the « missing-self » in solid organ rejection places HLA-C as an inescapable actor in transplant tolerance.Read less <