We present a case of a female patient with fibromyalgia and major depression refractory to medication treatment and experiencing severe side effects. In this case, GeneSight combinatorial pharmacogenomic testing was used to help guide further treatment. Pharmacogenomics is a tool that describes the variability in human genetic composition and how it can affect an individual’s response to medications. Ineffective medication responses and side effects are sometimes attributable to a patient’s pharmacokinetic or pharmacodynamic susceptibilities. Individuals vary in their ability to metabolize medications because of genetic variations on their pharmacokinetic genes, particularly in cytochrome P450 enzymes (CYPs) or Uridine 5'-diphospho-glucuronosyltransferases (UGTs). Efficacy and side effects can also be affected by polymorphisms in pharmacodynamic genes, coding for proteins directly related to the mechanism of action of medications such as the SLC6A4 serotonin transporter. GeneSight results showed she had multiple unusual polymorphisms that explained her lack of clinical response and her serious side effects. She was an ultrarapid metabolizer for CYP2D6, CYP2B6, CYP2C19, and UGT1A4 enzymes, as well as an intermediate metabolizer for UGT2B15. She also had an increased sensitivity to certain SSRIs due to her HTR2A genotype and an intermediate response to SSRIs due to her carrier status of the short form of the SLC6A4. These results were used to define a new approach to her care. After treatment adjustments based on the patient’s specific genetic profile, she has successfully reduced the number of medications taken from 19 daily medications to 2 daily medications and 2 as needed medications.