Oncolytic viruses represent a novel class of therapeutic agents that promote anti-tumor responses through a dual mechanism: selective tumor cell killing and induction of systemic anti-tumor immunity. The molecular and cellular mechanisms of action are complex, involving viral replication within transformed cells, induction of primary cell death, interaction with tumor cell antiviral elements, and initiation of innate and adaptive anti-tumor immunity. Various native and genetically modified viruses have been developed as oncolytic agents, with the first oncolytic virus expected to receive FDA approval soon. This review provides a comprehensive overview of the basic biology supporting oncolytic viruses as cancer therapeutics, describes their advanced clinical trials, and discusses unique challenges in their development. Oncolytic viruses can exploit cancer immune evasion pathways, modify the tumor microenvironment, and induce systemic anti-tumor immunity. They can also target unique cell surface receptors expressed by cancer cells and exploit aberrant signaling pathways in cancer cells. Strategies to enhance their effectiveness include targeting oncolytic viruses to cancer cells, exploiting aberrant signaling pathways, and limiting antiviral immune responses. The review also discusses the clinical development of oncolytic viruses, highlighting the progress made in Phase III trials.Oncolytic viruses represent a novel class of therapeutic agents that promote anti-tumor responses through a dual mechanism: selective tumor cell killing and induction of systemic anti-tumor immunity. The molecular and cellular mechanisms of action are complex, involving viral replication within transformed cells, induction of primary cell death, interaction with tumor cell antiviral elements, and initiation of innate and adaptive anti-tumor immunity. Various native and genetically modified viruses have been developed as oncolytic agents, with the first oncolytic virus expected to receive FDA approval soon. This review provides a comprehensive overview of the basic biology supporting oncolytic viruses as cancer therapeutics, describes their advanced clinical trials, and discusses unique challenges in their development. Oncolytic viruses can exploit cancer immune evasion pathways, modify the tumor microenvironment, and induce systemic anti-tumor immunity. They can also target unique cell surface receptors expressed by cancer cells and exploit aberrant signaling pathways in cancer cells. Strategies to enhance their effectiveness include targeting oncolytic viruses to cancer cells, exploiting aberrant signaling pathways, and limiting antiviral immune responses. The review also discusses the clinical development of oncolytic viruses, highlighting the progress made in Phase III trials.