The FOXO forkhead transcription factors are involved in metabolism control, cell survival, cellular proliferation, DNA damage repair response, and stress resistance. Their transcriptional activity is regulated through a number of posttranslational modifications, including phosphorylation, acetylation and ubiquitination. The recently determined three-dimensional structures of FOXO forkhead domains bound to DNA enable to explain the structural basis for DNA recognition by FOXO proteins and its regulation. The aim of this review is to summarize the recent structural characterization of FOXO proteins, the mechanisms of DNA recognition and the role of posttranslational modifications in the regulation of FOXO DNA-binding properties. This article is part of a Special Issue entitled: PI3K-AKT-FOXO axis in cancer and aging.