The genetic analysis of the Foxa genes in both total and conditional mutant mice has clearly established that organogenesis of multiple systems is controlled by this subfamily of winged helix transcription factors. These discoveries followed the establishment of the conceptional framework of the mechanism of action of the FoxA proteins as ‘pioneer factors’ that can engage chromatin before other transcription factors. Recent molecular and genomic studies have also shown that FoxA proteins can facilitate binding of several nuclear receptors to their respective targets in a context-dependent manner, greatly increasing the range and importance of FoxA factors in biology.