Oncolytic virotherapy opens up avenues for cancer treatment by selectively targeting the cancer cells and destructs them either through direct lysis or by inducing an immune response in the tumor microenvironment. This platform technology utilizes a diverse range naturally existing or genetically modified oncolytic viruses for their immunotherapeutic potential. Due to the limitations associated with the conventional cancer therapies, immunotherapies using oncolytic viruses (OVs) have generated a great deal of interest in the modern era. Currently, several oncolytic viruses have entered clinical trials and have proven successful for a number of different cancers as monotherapies as well as in combination with the standard treatment methods like chemotherapy, radiotherapy, or immunotherapy. Efficacy of OVs can be further enhanced by utilizing several approaches. Efforts of the scientific community for getting better knowledge of individual patient tumor immune responses will enable medical community to treat cancer patients more precisely. In this regard, OV seems to be a part of multimodality cancer treatment option in the near future. In this chapter, the fundamental characteristics and mechanism of actions of oncolytic viruses are initially described and then overview of the important clinical trials of various oncolytic viruses for a number of cancers is presented.