Genes that are highly expressed in cancer cells and are essential for their viability are attractive targets for the development of novel cancer therapeutics. Activating transcription factor 5 (ATF5) is an anti-apoptotic protein that is highly expressed in malignant glioma but not normal brain tissues, and is essential for glioma cell survival. Recent work has revealed an essential survival pathway mediated by ATF5 in malignant glioma; pharmacological inhibition of this pathway leads to tumor regression in mice. ATF5 is also highly expressed in a variety of other cancers, and preliminary studies have shown that the ATF5-mediated survival pathway is active in diverse human cancer cell lines. Targeting this pathway may therefore have therapeutic implications for the treatment of a wide range of cancers. In this perspective, we summarize recent advances in ATF5 research, focusing on its role in promoting cancer and its potential as a target for cancer therapy.