The introduction of immunosuppressive therapy has revolutionised liver transplantation, allowing for excellent long-term survival. However, it is often a fine balance between under and over immunosuppression, with the development of rejection and significant side effects respectively. Although immunosuppression protocols are still widely used, it is becoming apparent that significant proportion of patients will not benefit from such a blanket approach. For instance, patients with renal impairment may benefit from minimization of calcineurin inhibitor, whereas those transplanted for hepatocellular carcinoma may benefit from the use of mTOR inhibitors. Similarly, those with metabolic syndrome may benefit from the use of immunosuppressive agents not associated with the development of hypertension, hyperlipidemia, and diabetes mellitus. Although no new immunosuppressive agent has been approved for liver transplantation for almost a decade, there is still opportunity to individualize immunosuppression so that the greatest benefit can be derived for liver transplant recipients.