Background: Epitranscriptomics—the study of chemical modifications on RNA—has emerged as a pivotal layer of gene expression regulation. Among the most prevalent modifications are N6-methyladenosine (m6A) and 5-methylcytosine (m5C), which govern RNA stability, splicing, translation, and nuclear export. Disruptions in these modifications are increasingly recognized as drivers of oncogenesis and determinants of pharmacological response. Objective: This review synthesizes current evidence on the mechanistic roles of m6A and m5C in modulating drug sensitivity and resistance, focusing on their writers, erasers, and readers, and evaluating their therapeutic relevance across solid tumors and hematologic malignancies. Methods: A comprehensive literature search was conducted in PubMed, Embase, and Web of Science databases (2012–2024) using the terms: epitranscriptomics, m6A, m5C, drug resistance, chemotherapy resistance, and RNA methylation. Articles selected were peer-reviewed primary research articles, systematic reviews, and clinical studies. Results: m6A modifications mediated by METTL3/METTL14 writers and FTO/ALKBH5 erasers regulate downstream oncogenes and tumor suppressors implicated in cisplatin, doxorubicin, and tyrosine kinase inhibitor resistance. m5C, deposited by NSUN2 and TRDMT1, modulates translation fidelity and RNA stability in immune evasion and drug efflux contexts. Both marks show context-dependent, tumor-type-specific effects, complicating their therapeutic targeting. Conclusion: m6A and m5C represent promising, druggable targets whose manipulation could resensitize refractory tumors. Standardized detection methodologies, biomarker validation, and well-designed clinical trials are urgently needed to translate these discoveries into actionable clinical strategies.