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Critically ill patients often are at high-risk for adverse drug reactions (ADRs), mainly due to alterations in pharmacokinetic and pharmacodynamic (PK/PD) parameters. These PK/PD differences in can also lead to inadequate therapeutic response to many commonly used drugs in this patient population. Frequently in the critically ill patient, medications are utilized based on a "trial-and-error" approach. Furthermore, drug dosing in the critically ill largely remains a "one-size-fits-all" phenomenon, utilizing dosing based on PK studies in healthy volunteers. Known differences in gene variation among the general population can greatly alter response to drug therapy. The use of pharmacogenomics (PGX) to aid in the development of individualized pharmacotherapeutic regimens, potentially may reduce ADRs and increase therapeutic efficacy. Potential uses of PGX include: identification of patients who are particularly susceptible to ADRs; and patients whom are more likely to benefit from a particular drug therapy, based on the patient's own genetic profile. This review will focus on potential applications of PGX in the critically ill, including management of acute coronary syndromes (ACS), invasive fungal infections, and pain management. Current barriers to PGX-guided therapy in the critically ill and recent patent developments in the clinical application of PGX will also be discussed.