Nonoperative management is the treatment of choice for the vast majority of humeral shaft fractures. Good or excellent outcomes are reported in 85% to 95% of patients. However, the superiority of operative treatment has been demonstrated in several clinical scenarios, including open fractures, pathologic fractures, fractures in multiple-trauma patients, and fractures with associated intra-articular extension or neurovascular injuries. Operative management of humeral shaft fractures is also a viable option after failure to obtain or maintain acceptable fracture alignment by closed means, in cases of associated ipsilateral or contralateral upper extremity fractures, and for treatment of malunited or nonunited fractures. Osteosynthesis with plates and intramedullary nailing have been advocated, and multiple devices and surgical approaches are available for both techniques—each with particular advantages and disadvantages. Although there are few controlled studies comparing the various surgical treatment options, most authors report that intramedullary nailing may be associated with slightly higher rates of complications, particularly postoperative shoulder pain and impingement when using the antegrade approach, and elbow dysfunction when using the retrograde approach. We recommend plate fixation for most operatively treated humeral shaft fractures, particularly those with distal extension, nerve injury, or vascular injury. Nailing is preferred for fractures with proximal extension, segmental or significantly comminuted fractures, pathologic fractures, and humeral shaft fractures associated with significant soft tissue compromise. Key areas for future studies include entry site morbidity associated with intramedullary nailing, patient-perceived impact on quality-of-life, economic impact of humeral shaft fractures, and treatment alternatives.