Currently, there is a growing concern surrounding the treatment of cancer, a formidable disease. Pharmacogenomics and personalized medicine have emerged as significant areas of interest in cancer management. The efficacy of many cancer drugs is hindered by resistance mechanisms, particularly P-glycoprotein (P-gp) efflux, leading to reduced therapeutic outcomes. Efforts have intensified to inhibit P-gp efflux, thereby enhancing the effectiveness of resistant drugs. P-gp, a member of the ATP-binding cassette (ABC) superfamily, specifically the multidrug resistance (MDR)/transporter associated with antigen processing (TAP) sub-family B, member 1, utilizes energy derived from ATP hydrolysis to drive efflux. This review focuses on genetic polymorphisms associated with P-gp efflux and explores various novel pharmaceutical strategies to address this challenge. These strategies encompass SEDDS/SNEDDS, liposomes, immunoliposomes, solid lipid nanoparticles, lipid core nanocapsules, microemulsions, dendrimers, hydrogels, polymer-drug conjugates, and polymeric nanoparticles. The article aims to elucidate the interplay between pharmacogenomics, P-gp-mediated drug resistance in cancer, and formulation strategies to improve cancer therapy by tailoring formulations to genetically susceptible patients.