For years, developmental biologists have been trying to understand how positional information controls the development of vertebrate limbs. New insights into this three-dimensional puzzle are provided by Capellini and co-workers on p. 2263, who reveal that the homeoproteins Pbx1/Pbx2 regulate distal limb patterning in mice. Pbx1 is essential for proximal limb development but Pbx2-deficient embryos have normal limbs. The researchers now show that compound Pbx1–/–, Pbx2+/– mutant embryos have severe distal limb abnormalities–the fibula and most of the digits are lost in the hindlimb–in addition to exacerbated proximal abnormalities. This distal phenotype resembles that seen in embryos that lack sonic hedgehog (Shh), and indeed, the loss of skeletal elements in mutant hindlimbs is mediated by the absence of Shh. This deficit is preceded by a severe perturbation of Hox gene expression. The researchers conclude,therefore, that Pbx1/Pbx2 regulate vertebrate distal limb patterning partly by controlling the spatial expression of Hox genes and Shh expression.