Human leukocyte antigen G (HLA-G) is a non-classic major histocompatibility complex (MHC) class I molecule that functions as an immune suppressive molecule. HLA-G has direct inhibitory effects on natural killer cells (NK), dendritic cells (DC), T cells and has long-term tolerogenic indirect effects by inducing regulator T cells (Treg). HLA-G has been reported to be involved in various physio-pathological conditions such as reproduction, transplantation, autoimmunity, infectious and malignant diseases. In this context, aberrant expression of HLA-G in malignant diseases including hematological and solid tumors has been extensively investigated and its relevance to clinicoparameters and potential significance in diagnosis, prognosis and immune target therapy has been postulated. We here summarized the HLA-G expression in malignancies and emphasis its clinical relevance to malignant disease diagnosis, prognosis, and its potential in target-based immunotherapy was also discussed.