Tumors are complex tissues composed of different cell types that interact with one another by building up complicated intra-and intercellular signal networks. In addition to the proliferating cancer cells, tumors also contain normal cells which are recruited and eroded by cancer cells to form tumor-supportive stroma and these natively normal stromal cells actively participate in the tumor development and progression by editing some of the behaviors of cancer cells and creating a tumor microenvironment to foster the rapid growth and proliferation of cancer cells. Therefore, the genetically mutated cancer cells are the cell of origin and driving forces for tumor development and progression. Selectively targeting cancer cells to induce tumor cell death and intercepting or normalizing the interaction signal network between the cancer and stromal cells are the bases for current cancer therapies. Identification of the mutated components in the intrinsic and extrinsic apoptotic pathways in cancer cells and designing small molecule mimetics or agonists to eradicate cancer cells by selectively targeting these mutations represent the attractive strategies for modern cancer therapy.