Total Knee Arthroplasty (TKA) represents an effective technique to treat advanced and debilitating knee arthritis. However at long term follow-up the risk of TKA failure still remains a concern. Nowadays the major causes of failures and patient’s dissatisfaction, in addition to infection, are a prosthesis that remains instable or is not well aligned on sagittal, transverse or coronal plane. All these situations, in fact, could lead to anterior knee pain, arthrofibrosis, wear or loosening. Therefore, was developed the Computer-Assisted Surgery (CAS), a device that helps the surgeon to position the prosthesis component in a much more accurate way than the conventional instrumentation. In fact, via intra-operative anatomy-based tracking of the tibio-femoral joint, CAS allows more precise bone cuts, more accurate prosthesis components implantation, more controlled soft tissue balance and targeted Mechanical Axis restoration. The aim of this chapter is to present and explain which are the main surgical landmarks of CAS, so how it works and how it could help the surgeon being much more precise with bone cuts and control instantly how the resections could influence the final alignment and the stability of the prosthesis.