The Six family transcription factors Six1 and Six2 play non-overlapping roles during kidney development in mice: Six1 controls the initial formation of nephron progenitors, which give rise to nephrons (the functional units of the kidney), whereas Six2 controls progenitor self-renewal. How these factors function during kidney development in humans, however, is less clear. Now, Lori O'Brien, Anton Valouev, Andrew McMahon and co-workers reveal that mouse and human nephron progenitors are differentially regulated by Six family factors (p. 595). Using ChIP-seq analyses, they show that, although mouse Six2 and human SIX2 share many common targets, the SIX1 gene is a unique SIX2 target in humans. In line with this, they demonstrate that Six1 expression is transient and independent of Six2 in the mouse embryonic kidney, whereas SIX1 expression persists in human fetal nephron progenitors and is regulated by SIX2. The researchers also show that SIX1 and SIX2 exhibit overlapping activities in human fetal nephron progenitors, binding to similar sets of targets and showing evidence of cross-regulatory activity. These findings highlight a divergence in Six family function that may underlie species-specific differences in kidney development, such as the extended period of nephrogenesis seen in humans.