Cisplatin remains a cornerstone of chemotherapy for numerous solid tumors; however, its clinical utility is frequently compromised by substantial inter-individual variability in treatment response and the emergence of severe dose-limiting toxicities. This review systematically examines the primary pharmacogenetic and epigenetic factors that underpin these differential clinical outcomes. We evaluated key polymorphisms in genes governing drug metabolism and transport; specifically, those of glutathione S-transferases (GSTs), copper transporters (CTR1, ATP7A/B), and solute carrier (SLC) transporters, which collectively dictate intracellular drug accumulation and inactivation. Furthermore, we analyzed the critical role of the DNA repair machinery, with a particular emphasis on the nucleotide excision repair pathway in mediating cisplatin resistance. Beyond traditional genetic variations, this review explored the emerging effect of epigenetic modifications and noncoding RNAs, including microRNAs, long noncoding RNAs, and circular RNAs, in post-transcriptionally modulating cellular pathways associated with chemoresistance. The synthesis of these findings underscores the need to integrate robust pharmacogenetic profiling into clinical practice to transition oncology from a standardized protocol to a personalized therapeutic approach. Ultimately, identifying and validating these molecular markers can maximize therapeutic efficacy while mitigating adverse toxicities in individual patients.