The human developmental Okihiro and Townes-Brocks syndromes are caused by mutations in SALL4 and SALL1, respectively, human homologs of the Drosophila homeotic gene spalt (sal). Both syndromes feature limb, kidney, heart and anal deformities. Now, on p. 3005,Sakaki-Yumoto et al. report that the mouse homologs of sal cooperate during anorectal, heart, brain and kidney development. To investigate the roles of mammalian Sal-related genes in organogenesis, the researchers studied mice carrying mutations in these genes. Unexpectedly, they discovered that Sall4 is essential for embryonic stem cell proliferation and early embryogenesis. Sall4 haploinsufficiency, however, causes anorectal and heart defects; Sall4/Sall1 compound heterozygotes have an increased incidence of these abnormalities, plus brain and kidney defects. Consistent with this genetic interaction, the researchers found that Sall4 and Sall1 form heterodimers. Furthermore, truncated Sall1 prevents the normal localisation of Sall4 to heterochromatin. Because SALL1 is truncated in Townes-Brocks patients, the authors suggest that certain abnormalities associated with this disease might be caused by SALL1 inhibiting SALL4.