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Oncolytic viruses as anticancer agents: clinical progress and remaining challenges. Immunotherapy has transformed the treatment of cancer, yet many patients do not have response or lasting benefit. Strategies to overcome resistance remain of crucial importance. Oncolytic viruses offer a promising approach, with the unique ability to selectively replicate within (and to destroy) cancer cells, remodel the immunosuppressive tumour microenvironment, and stimulate antitumour immunity. Interest in the potential of oncolytic viruses has grown steadily over the past two decades, fuelled by advances in cancer immunology and viral engineering. However, clinical translation has not kept pace, and although a plethora of promising new constructs have entered clinical testing, several barriers continue to restrict widespread clinical implementation. This Therapeutics paper highlights key milestones in oncolytic virus clinical development, discusses the challenges that remain, and, through clinical reflection, considers how future research might be streamlined to achieve meaningful benefit for patients.