Oncolytic viruses are a unique group of viruses that – either naturally or through genetic modification – induce the destruction of cancer cells. With improved knowledge of viral genomics and genetic modification technology over the past two decades, oncolytic viruses have emerged as a promising platform for cancer therapeutics. Three core aspects of oncolytic viruses include (1) their cytopathic effects on tumor cells; (2) their ability to stimulate the immune system to enhance antitumor immunity; and (3) their synergy with other modalities of oncologic treatment. Notably, different families of oncolytic viruses have distinct advantages deriving from their physical structures, as some have large DNA genomes amenable to genetic recombination while others are small and able to cross blood brain barriers. To date, four viruses have been approved globally for use in melanoma, malignant glioma, and head and neck squamous cell carcinoma: Rigvir®/ECHO-7 (2004), Oncorine®/H101 (2005), IMLYGIC®/T-VEC (2015), and DELYTACT®/Teserpaturev/G47Δ (2021), with numerous others actively undergoing clinical trials. This chapter provides an overview of the history of oncolytic viruses, their mechanisms of action, as well as their synergies with other modalities of cancer treatment. Different viral families commonly used as oncolytic viruses and details on the four oncolytic viruses clinically approved for cancer treatment are also discussed.