This article serves to provide an overview of molecular and surgical interventions to minimize the progression of posttraumatic arthritis following high-energy intra-articular fractures. The roles of cartilage and the microcellular environment are discussed, as well as the response of the joint and cartilage to injury. Molecular therapies, such as glucocorticoids, mesenchymal stem cells, and bisphosphonates, are presented as potential treatments to prevent progression to posttraumatic arthritis. High-energy intra-articular fractures of the elbow, hip, knee, and ankle are discussed, with emphasis on restoring anatomic alignment, articular reduction, and stability of the joint.