Background: Precision medicine has become increasingly critical in cancer supportive care, with implications for treatment selection, medication dosing, and side effect prediction. The presence of clinically actionable germline variants brought the hope that accurate prediction of drug efficacy and toxicity would be in the future. This will greatly improve the comprehensive oncology care, where supportive care treatment options can be subjective and personalized. Methods: The changes in drug effect and toxicity caused by genetic variations were characterized in 4,287 patients submitted for clinical pharmacogenetics testing using a gene panel including key pharmacokinetic and pharmacodynamic genes. For each patient, the need to select an alternate medication and adjust medication dose was determined for the treatment of pain (CYP2D6, CYP1A2, OPRM1), nausea/vomiting (CYP2D6), antifungal prophylaxis (CYP2C19), and depression (CYP2D6, CYP2C19). It is recognized that there are many other factors playing in the variations of the response and toxicity to these classes of medications. Results: Of the 4,287 patients, 964 (22%) would have a recommendation to choose alternatives of oxycodone, codeine, or tramadol therapy and 3,394 patients (79%) for a non-standard dosage. A change in certain antiemetics such as ondansetron would be suggested for 171 patients (4%). If voriconazole antifungal prophylaxis was clinical required, 1,228 (29%) would need a dose increase, while 133 (3%) should be switched to a different regimen. 2,727 patients (64%) should avoid or adjust dosage on some of the commonly used agents for depression due to reduced efficacy or heightened risk of toxicity. Conclusions: Pharmacogenetics markers associated with reduced drug efficacy and higher rate of ADRs were commonly observed for medications used in cancer supportive care. Identification of these markers would help clinicians achieve optimal treatment outcome with manageable time and cost. This provides great opportunities to apply precision medicine principles to patient management.