•Regulation of CD73 expression in cancer cells.•Regulation of CD73 on host cells.•Prognostic impact of CD73 in cancer.•Overview of CD73 targeting agents in clinical trials. The ectonucleotidases CD39 and CD73 are cell surface enzymes that catabolize the breakdown of extracellular ATP into adenosine. As such, they constitute critical components of the extracellular purinergic pathway and play important roles in maintaining tissue and immune homeostasis. With the coming of age of cancer immunotherapy, ectonucleotidases and adenosine receptors have emerged as novel therapeutic targets to enhance antitumor immune responses. With early-phase clinical trials showing promising results, it is becoming increasingly important to decipher the distinct mechanisms-of-action of adenosine-targeting agents, identify patients that will benefit from these agents and rationally develop novel synergistic combinations. Given the broad expression of ectonucleotidases and adenosine receptors, a better understanding of cell-specific roles will also be key for successful implementation of this new generation of immuno-oncology therapeutics. We here review the latest studies on the roles of CD73 and adenosine in cancer with a focus on cell-specific function. We also discuss ongoing clinical trials and future avenues for adenosine-targeting agents.