Background: Numerous surgical options exist to treat chondral lesions in the knee, including microfracture (MFx), osteochondral autograft transplantation (OAT), first-generation autologous chondrocyte implantation (ACI-1), and next-generation ACI (ACI-2). Purpose: To compare the cost-effectiveness of MFx, OAT, and ACI-1. The secondary purpose of this study was to compare the functional outcomes of MFx, OAT, ACI-1, and ACI-2. Study Design: Systematic review; Level of evidence, 2. Methods: Two independent reviewers conducted an online literature search of 2 databases for level 1 and 2 studies using the Lysholm, International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), and/or Hospital for Special Surgery (HSS) Knee Score. A weighted mean difference in pre- to postoperative functional outcome score was calculated for each treatment. The mean per-patient costs associated with MFx, OAT, and ACI-1 were determined from a recent publication based on review of a national private insurance database. The cost for each procedure was then divided by the weighted mean difference in functional outcome score to give the cost-per-point change in outcome score. Results: A total of 12 studies (6 level 1, 6 level 2) met the inclusion criteria for the functional outcome analysis, including 730 knees (MFx, n = 300; OAT, n = 90; ACI-1, n = 68; ACI-2, n = 272). The mean follow-up was not significantly different between groups (MFx, 29.4 months; OAT, 38.3 months; ACI-1, 19.0 months; ACI-2, 26.7 months). The mean increase in functional outcome score was 23 for MFx, 19 for OAT, 20 for ACI-1, and 35 for ACI-2. The change in functional outcome score was significantly greater for ACI-2 when compared with all other treatments (P < .0001). The cost-per-point change in functional outcome score was $200.59 for MFx, $313.84 for OAT, and $536.59 for ACI-1. Conclusion: MFx, OAT, ACI-1, and ACI-2 are effective surgical procedures for the treatment of cartilage defects in the knee. All 4 treatments led to an increase in functional outcome scores postoperatively with a short-term follow-up. ACI-2 had a statistically greater improvement in functional outcome scores as compared with the other 3 procedures. MFx was found to be the most cost-effective treatment option and ACI-1 the least cost-effective.