Activation of mitochondria-mediated apoptosis represents a major anti-tumor response of p53. One of the mechanisms for p53 to induce mitochondria-mediated cell death events is to activate genes that are directly involved in the initiation of mitochondria-induced apoptosis. Among them are Bcl-2 family members, Noxa, PUMA, and Bax. They have been shown to be direct targets in p53-mediated apoptosis. The Bax protein belongs to the multidomain Bcl-2 family, while Noxa and PUMA are BH3-domain-only proteins. This review focuses on discussing the function of these protein in p53-mediated apoptosis and how they contribute to the decision making of p53 response: growth arrest or apoptosis.