Calcineurin inhibitor-induced pain syndrome (CIPS), a rare but recognized complication of calcineurin inhibitor (CNI) therapy in transplant recipients, presents as severe bilateral lower extremity pain. This syndrome, first described in 1989, primarily affects patients receiving tacrolimus or cyclosporine. Proposed mechanisms include intraosseous vasoconstriction, bone marrow edema, and altered bone metabolism, possibly involving TRSK channels and NFAT signaling. The diagnosis relies on clinical history, characteristic pain patterns, and imaging findings such as bone marrow edema on MRI. The management of CIPS revolves around reducing or discontinuing the offending CNI while maintaining immunosuppression. Alternative immunosuppressants like mammalian target rapamycin (mTOR) inhibitors or mycophenolate mofetil are considered to mitigate symptoms. Symptomatic relief includes calcium channel blockers, bisphosphonates, and analgesics like NSAIDs or opioids. Physical therapy and close monitoring are also integral to improving outcomes and managing chronic pain effectively in affected transplant recipients. This review synthesizes current knowledge on CIPS, highlighting diagnostic challenges, treatment options, and areas for future research to optimize clinical management and enhance patient outcomes.