Perioperative pain management after knee arthroplasty has undergone a conceptual revolution in the last decade. Along with other exciting innovations, including minimally invasive techniques, computer-assisted procedures and a significant stride in tribology, understanding pain modulation and drug action at a molecular level is recognized as the game changer in arthroplasty surgeries. While most patients usually recover and experience pain relief within 3 mo after TKA, about 20% (10–34%) of the patients are left with an unfavorable long-term pain outcome. Fifty-two percent of patients report moderate pain and 16% report severe pain at rest 30 days after TKA, while pain at movement affects as much as 78% of the patients. Inability to adequately control postoperative pain causes undue suffering, inability to participate in fast-track rehabilitation programs, sleep disturbance (44% patients first 3 nights), delayed discharge, and the development of persistent postsurgical pain. The goal of this review article is to give an overview of the fundamental concept of surgical pain, the molecular mechanism of action of different drugs, evolution of the concept of preventive analgesia, and state of the art for current pain management. When combined and standardized, these factors allow arthroplasty surgeons to offer outpatient arthroplasty procedures.