BACKGROUND: There is still a lack of consensus about the best treatment of chondral defects of the knee. We conducted a systematic PRISMA review to evaluate clinical outcomes of Autologous Chondrocyte Implantation (ACI) and Mesenchymal Stem Cell (MSC) injections for the treatment of focal chondral defects of the knee. METHODS: A systematic review of literature was performed according to the PRISMA guidelines. All the articles reporting data on ACI and MSC treatments for chondral defects of the knee were considered for inclusion. The main databases were accessed: PubMed, Medline, CINAHL, Cochrane, Embase and Google Scholar. The statistical analysis was performed using the Review Manager Software. RESULTS: In the p-ACI group (987 knees), the Cincinnati Score improved by 18.94% (p=0.1), VAS by 38% (p=0.01), Tegner score by 19.11% (p=0.03), Lysholm score by 22.40% (p=0.01), IKCD by 27.36% (p=0.003). In the c-ACI group (444 knees), the Cincinnati Score improved by 23.80% (p=0.08), KOOS by 23.48% (p=0.03), VAS by 33.2% (p=0.005), IKDC by 33.30% (p=0.005). In the m-ACI group (599 knees), the Cincinnati Score improved by 26.80% (p=0.08), KOOS by 31.59% (p=0.1), VAS by 30.43% (p=0.4), Tegner score by 23.1% (p=0.002), Lysholm score by 31.14% (p=0.004), IKCD by 30.57% (p<0.001). In the MSCs group (291 knees), the KOOS improved by 29.7% (p=0.003), VAS by 41.89% (p<0.001), Tegner score by 25.81% (p=0.003), Lysholm score by 36.96% (p<0.001), IKCD by 30.57% (p=0.001). CONCLUSION: Both ACI and MSC therapies can be considered as a concrete solution to treat focal chondral defects of the knee.