Current evidence suggests at least one-third of humeral shaft fractures initially managed nonoperatively will fail closed treatment, and this review highlights surgical considerations in those circumstances. Although operative indications are well-defined, certain fracture patterns and patient cohorts are at greater risk of failure. When operative intervention is necessary, internal fixation through an anterolateral approach is a safe and sensible alternative. Determining which patients will benefit most involves shared decision-making and careful patient selection. The fracture characteristics, bone quality, and adequacy of the reduction need to be carefully evaluated for the specific operative risks for individuals with certain comorbid conditions, inevitably balancing the patient's expectations and demands against the probability of infection, nerve injury, or nonunion. As our understanding of the etiology and risk of nonunion and symptomatic malunion of the humeral diaphysis matures, adhering to the principles of diagnosis and treatment becomes increasingly important. In the event of nonunion, respect for the various contributing biological and mechanical factors enhances the likelihood that all aspects will be addressed successfully through a comprehensive solution. This review further explores specific strategies to definitively restore function of the upper extremity with the ultimate objective of an uninfected, stable union.