In patients who undergo breast reconstruction after mastectomy, choosing the appropriate timing and the best method of reconstruction are essential to optimize outcomes and to minimize the potential for postoperative complications. At The University of Texas M. D. Anderson Cancer Center, the clinicopathologic factors that are used in the surgical decision-making for breast reconstruction after mastectomy include the breast cancer stage, status of axillary sentinel lymph node, smoking status, body habitus, preexisting scars, prior radiation therapy, and planned or previous chemotherapy. Immediate breast reconstruction after mastectomy is preferable for patients who have a low risk of requiring postmastectomy radiation therapy (PMRT) (Stage I breast cancer). Delayed reconstruction may be preferable in patients who are deemed preoperatively to require PMRT (Stage III breast cancer) to avoid difficulties associated with radiation delivery after an immediate breast reconstruction. In patients who are deemed preoperatively to be at an increased risk of requiring PMRT (Stage II breast cancer), delayed-immediate breast reconstruction may provide an additional option. The approach to breast reconstruction will need to be adapted to maintain an appropriate balance between minimizing the risk of recurrence and providing the best possible aesthetic outcomes as the indications for PMRT and other treatment modalities continue to change.