Tissue ischemia can be managed in several different ways based on the cause of the perfusion defect, including topical nitroglycerin or surgical intervention. However, there are times when tissue perfusion is questioned and clinical examination is unable to determine definitively the cause of ischemic tissue and whether it will survive. In this technique article, we describe our comprehensive algorithm for the management of tissue ischemia in mastectomy skin flaps, which can be applied to other plastic surgery procedures by integrating SPY angiography and topical nitroglycerin.