Liver transplantation (LT) has witnessed continuous improvements in outcomes over the past decades; however, long-term survival rates still fall short of those observed in the general population. Indeed, while increasing the potency of immunosuppressive agents in LT has drastically reduced the rates of steroid-resistant rejection and rejection-related graft loss, an emerging conundrum is the extended exposure of transplant recipients to these powerful agents, driven by both their heightened benefits and the prolonged survival of recipients. This juxtaposition manifests as a double-edged sword, whereby increased immunosuppressive potency combats rejection but exposes recipients to undesirable adverse effects. Individualizing the selection and titration of immunosuppressive drugs is a critical endeavor aimed at effectively managing alloreactivity while mitigating the burden of toxicities. Although routine laboratory tests fall short in providing a confident diagnosis of allograft rejection, the landscape of biomarkers holds promise. However, these biomarkers are yet to attain the level of validation required for routine clinical use, necessitating the retention of liver biopsy as a guiding tool for clinical decisions. Understanding the mechanisms of action and adverse effects of commonly used immunosuppressive drugs is pivotal. This review delves into the intricacies of various immunosuppressive regimens for both early and maintenance phases. Achieving the delicate balance between optimal immunosuppression (IS) for rejection prevention and minimizing immunosuppressive-related adverse effects requires the fusion of medical science and clinical expertise. Strategies focused on preserving renal function, averting recurrent or de novo cancer, and recurrent or de novo immune-mediated diseases, as well as tackling metabolic syndrome, are explored in this context.