Anterior cruciate ligament (ACL) reconstruction has the best chance for success when the graft undergoes extensive biologic remodeling and incorporation after implantation. There are many factors that can lead to graft failure and possible revision surgery. These include patient selection; surgical technique such as graft placement and tensioning; the use of allograft versus autograft; mechanical factors such as secondary restraint laxity; lack of a correct, carefully controlled post-operative rehabilitation program; and biological factors. When a patient presents with knee instability following ligament reconstruction and there is no history of a new trauma or identifiable technical error, biological failure should be considered. However, the biologic response of the grafted tissue is closely linked to the mechanical and biochemical environment into which the graft is placed. Thus, the "biological failure" of the ACL graft is a complex pathological entity whose cause is not fully understood. Failure may be initiated by early extensive graft necrosis, disturbances in revascularization, problems in cell repopulation and proliferation, and as well difficulties in the ligamentization process. However, further study of the biological characterization of a failed graft placed in a correct mechanical environment is warranted.