Cancer drug resistance has emerged as a formidable challenge in the field of clinical oncology, significantly hampering the success of treatment strategies and leading to suboptimal outcomes for patients. In a broad array of therapeutic settings, the emergence of resistance has become a primary source of concern, ranging from conventional chemotherapy to modern immunotherapy and targeted therapies. The complexity of cancer drug resistance is further exacerbated by the involvement of oncoviruses, such as human papillomavirus (HPV), Epstein-Barr virus (EBV), and hepatitis B virus (HBV), which play pivotal roles in the initiation, progression, and response to treatment of various cancers. The intricate interactions between these oncoviruses and cancer cells have been found to significantly influence drug efficacy. These viruses can alter critical cellular pathways, including drug metabolism, DNA repair mechanisms, and the tumor microenvironment, thus promoting drug resistance. A profound understanding of these virus-cancer-drug interactions is crucial for the development of novel treatment approaches that can effectively overcome drug resistance. This review aimed to contribute to a broader awareness of the multifaceted nature of cancer drug resistance, particularly in the context of oncovirus involvement. By highlighting the critical role of oncoviruses in cancer development and treatment response, this review hopes to stimulate further research and the development of novel treatment strategies that can effectively overcome drug resistance and ultimately improve patient outcomes. As we advance toward precision oncology, a more holistic understanding of the complex interplay among cancer, its associated viruses, and therapeutic drugs is crucial for achieving optimal therapeutic responses.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.