The management and treatment of cartilage lesions, osteochondral defects, and osteoarthritis remain a challenge in orthopedics. Moreover, these entities have different behaviors in different joints, such as the knee and the ankle, which have inherent differences in function, biology, and biomechanics. There has been a huge development on the conservative treatment (new technologies including orthobiologics) as well as on the surgical approach. Some surgical development upraises from technical improvements including advanced arthroscopic techniques but also from increased knowledge arriving from basic science research and tissue engineering and regenerative medicine approaches. This work addresses the state of the art concerning basic science comparing the knee and ankle as well as current options for treatment. Furthermore, the most promising research developments promising new options for the future are discussed.