An estimated 182,640 women and 1,990 men were diagnosed with breast cancer in 2008, and approximately 40,480 women and 450 men died from the disease. Thus, continued mechanistic studies are needed to understand the causes and develop additional therapeutics for this complicated disease. The MCF-7 cell system is one of the most recognized models for estrogen receptor (ER)-positive breast cancer and has generated approximately 13,000 publications cited in PubMed to date. A number of clues for biological mechanisms related to apoptotic/anti-apoptotic pathways and chemoresistance were elucidated and summarized in our previous review. The focus of this review is new knowledge of the central role of sphingolipid signaling in apoptotic mechanisms in estrogen receptor-positive breast cancer. The ultimate goal is to target crucial steps in survival signaling pathways that may ultimately provide additional translational solutions to the successful pharmacologic treatment of breast cancer.