Fibrates are a medication class prescribed for decades as ‘broad-spectrum’ lipid-modifying agents used to lower blood triglyceride levels and raise high-density lipoprotein cholesterol levels. Such lipid changes are associated with a decrease in cardiovascular disease, and fibrates are commonly used to reduce risk of dangerous cardiovascular outcomes. As with most drugs, it is well established that response to fibrate treatment is variable, and this variation is heritable. This has motivated the investigation of pharmacogenomic determinants of response, and multiple studies have discovered a number of genes associated with fibrate response. Similar to other complex traits, the interrogation of single nucleotide polymorphisms using candidate gene or genome-wide approaches has not revealed a substantial portion of response variation. However, recent innovations in technological platforms and advances in statistical methodologies are revolutionizing the use and integration of other ‘omes’ in pharmacogenomics studies. Here, we detail successes, challenges, and recent advances in fibrate pharmacogenomics.