Breast reconstruction using prosthetic devices is the most commonly performed procedure in women following mastectomy. The goal is to provide an outcome that is predictable and reproducible while minimizing complications and optimizing aesthetics. There are various strategies by which this can be achieved. It begins with proper patient selection because most adverse events occur in high-risk patients. This in turn is related to the timing of the reconstruction that can be performed immediately following the mastectomy or on a delayed basis. Many surgeons have been combining the use of acellular dermal matrices with prosthetic devices that require strict attention to detail to ensure success. There are various options for achieving device coverage that include total muscle, partial muscle, and subcutaneous coverage. The radiated patient poses additional challenges and limitations that must be understood to achieve a desired outcome. Finally, autologous fat grafting has become a valuable tool to improve outcomes in both radiated and non-radiated women. These factors will be reviewed with the intent of improving outcomes and minimizing complications in the setting of prosthetic breast reconstruction. J. Surg. Oncol. 2016;113:895–905. © 2016 Wiley Periodicals, Inc.