With the advent of effective immunosuppression, short-term outcomes after liver transplant (LT) have improved drastically, while long-term outcomes remain static at around 75% at 5 years. This is predominantly linked to complications related to immunosuppressive drugs, which could be drug-specific, class-specific, or generic. The backbone of immunosuppression post-LT, calcineurin inhibitors (cyclosporine and tacrolimus) are associated with most of the complications, including renal dysfunction, post-transplant diabetes mellitus (PTDM), and metabolic syndrome (MS). Development of diabetes, osteoporosis, and metabolic syndrome post-LT has been linked to the cumulative steroid dose. Infections post-LT and de novo malignancies (DNMs) are linked to the overall cumulative immunosuppression. These complications increase the healthcare costs, long-term morbidity and mortality, and hamper the quality of life of LT recipients. Thus, it is imperative that transplant physicians are made aware of the long-term risks of immunosuppression and strategies to mitigate these complications by keeping the immunosuppression at the lowest level while simultaneously preventing allograft rejection. This chapter provides clinicians with an updated, comprehensive review of the long-term complications of immunosuppression post-LT, associated risk factors, and ways to minimize these complications.