This mutually exclusive paradigm of P-gp functionality requires a more comprehensive and detailed understanding of its role in tumor microenvironment with active interplay of cancer and immune cells in the tumor mileu. In this review, we focus on the current understanding of the role of P-gp in cancer cells and immune cells and finally attempt to highlight some caveats in the current understanding of its role in comprehensive tumor microenvironment along with challenges in the development of P-gp inhibitors toward anti-cancer therapy. This evidence concerns the gene PGP and neoplasm.