Calcineurin inhibitors (CNIs) are a class of immunosuppressive drugs that are commonly used to prevent organ rejection after transplantation. However, they can cause adverse effects such as nephrotoxicity, neurotoxicity, gastrointestinal issues, and metabolic disturbances, particularly in high-risk patients. High-risk patients include older patients, patients with pre-existing medical conditions, and patients with longer ischemia times. Several strategies to manage CNIs in high-risk patients, including CNI dosing, CNI monitoring, alternative therapies, and strategies to minimize nephrotoxicity, are discussed in the presentation. Individualized management strategies can help reduce the risk of adverse effects and improve long-term outcomes in high-risk patients. By tailoring CNI dosing and monitoring to each patient's individual needs, the risk of adverse effects can be minimized. In conclusion, the new insights presented highlight the importance of individualized CNI management in high-risk patients after liver transplantation. Healthcare providers are encouraged to adopt individualized CNI management strategies in their practice to improve patient outcomes.