Over recent years, significant advances in cancer immunotherapy have been made due to a better understanding of the principles underlying tumor biology and immunology. In this context, ecto-5′-nucleotidase (CD73) is a key molecule, because the degradation of AMP into adenosine results in the generation of an immunosuppressed and pro-angiogenic niche within the tumor microenvironment that promotes the onset and progression of cancer. Targeting CD73 has resulted in favorable antitumor effects in preclinical models, and the combined treatment of CD73 blockade with other immune-modulating agents [i.e., anti-cytotoxic T lymphocyte antigen (CTLA)-4 monoclonal antibodies (mAb) or anti-programmed cell death protein (PD)-1 mAb] is a particularly attractive therapeutic option. Although there is still a long way to go, anti-CD73 therapy, through the development of CD73 mAb, could constitute a new biologic therapy for treating patients with cancer. In this review, we discuss the link between CD73 and the onset, development, and spread of tumors, highlighting the potential value of this molecule as a drug target and a novel biomarker in the context of personalized cancer therapy.