Cancer remains one of the most difficult life-threatening diseases to treat. Breast cancer was one of the deadliest diseases which occupies the second place in the list of cancers with the highest mortality rates. Despite many successes in cancer therapy, many tumors are not efficiently killed by chemotherapy, leading some to suggest that cancer cells are generally blocked the apoptotic signaling. Consequently, there are a plethora of studies that are trying to decipher the apoptotic processes deregulated in specific diseases. The Bcl-2 family proteins comprise the sentinel network that regulates the intrinsic apoptotic response. Clinical trials of several investigational drugs, targeting the Bcl-2 family, are ongoing which up to date confirmed the efficiency of these agents in killing cancer cells and overcoming chemotherapy resistance. Here, we review the role of the Bcl-2 family in apoptotic pathways and those agents that are known and/or designed to inhibit the anti-apoptotic Bcl-2 family of proteins.