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Regulatory networks controlling cellular plasticity, important during early development, can re-emerge after tissue injury and premalignant transformation. One such regulatory molecule is the cell surface ectoenzyme ecto-5'-nucleotidase that hydrolyzes the conversion of extracellular adenosine monophosphate to adenosine (eADO). Ecto-5'-nucleotidase (NT5E) or cluster of differentiation 73 (CD73), is an enzyme that is encoded by <i>NT5E</i> in humans. In normal tissue, CD73-mediated generation of eADO has important pleiotropic functions ranging from the promotion of cell growth and survival, to potent immunosuppression mediated through purinergic G protein-coupled adenosine receptors. Importantly, tumors also utilize several mechanisms mediated by CD73 to resist therapeutics and in particular, evade the host immune system, leading to undesired resistance to targeted therapy and immunotherapy. Tumor cell CD73 upregulation is associated with worse clinical outcomes in a variety of cancers. Emerging evidence indicates a link between tumor cell stemness with a limited host anti-tumor immune response. In this review, we provide an overview of a growing body of evidence supporting the pro-tumorigenic role of CD73 and adenosine signaling. We also discuss data that support a link between CD73 expression and tumor plasticity, contributing to dissemination as well as treatment resistance. Collectively, targeting CD73 may represent a novel treatment approach for solid cancers.