Injuries to the anterior cruciate ligament (ACL) frequently lead to early-onset osteoarthritis. Despite advancement in surgical techniques, ACL reconstruction has a limited ability to prevent these degenerative changes. While previous studies have investigated knee function after ACL reconstruction, in vivo investigations of the effects of graft placement on in vivo joint function and cartilage health are limited. This review presents a series of studies that used novel imaging and 3D modeling techniques to determine the in vivo placement of the ACL graft on the femur using two different ACL reconstruction techniques. These techniques resulted in two distinct graft placement groups: one where the ACL was placed anatomically near the center of the native ACL footprint and another where the graft was placed anteroproximally on the femur, centered outside the ACL footprint. We quantified the effects of graft placement on graft deformation during in vivo loading and how these variables affected knee motion. Finally, we quantified whether femoral placement of the graft affected cartilage thickness. Our results demonstrate that achieving anatomic graft placement on the femur is critical to restoring native ACL function and normal knee kinematics. Knees with grafts that more closely restored normal ACL function, and thus knee motion, experienced less focal cartilage thinning than did those that experienced abnormal knee motion. These results suggest that achieving anatomic graft placement is a critical factor in restoring normal knee motion and potentially slowing the development of degenerative changes after ACL reconstruction.