p53 is considered as the "master regulator" in DNA damage-induced cell apoptosis. However, p53 is the most frequently mutated gene in human cancers (more than 50 %). Thus the research of p53-independent pathway in cell apoptosis may ultimately provide new therapeutic opportunities for many cancers. It has been shown that Caspase 2, p73, p63, and NF-kappa B-related signaling pathways are involved in DNA damage-induced, p53-independent cell apoptosis. This article reviews the recent research progress in these signaling pathways.