The BCL-2 family is a key player in the balance between cell survival and cell death. Family members such as BCL-2, BCLXL, and MCL-1 are well known to be dysregulated in cancer, leading to a prosurvival advantage. Although attempts to inhibit specific BCL-2 member proteins have been partially successful, evolution of protein targets through upregulation/mutation, and signaling from the TME may ultimately lead to cell survival/progression.