The FoxO family of transcription factors mediate a wide range of cellular responses from cell death to cell survival, growth inhibition and glucose utilization. This complex array of responses is regulated by an equally complex regulatory system, involving phosphorylation, ubiquitinization and acetylation, in addition to interactions with other transcription factors and transcriptional modifiers. In heart, FoxO proteins have been shown to be involved in development in limiting hypertrophic growth responses and in cardioprotection provided by silent information regulator 1 (Sirt1). However, the range of responses mediated by FoxO proteins and the clear evidence for involvement of FoxO regulators in cardiac pathology, suggest that further pathological actions of FoxO family members remain to be elucidated.