Members of the Hedgehog (Hh) and Wnt/Wingless (Wg) families of secreted proteins control many aspects of growth and patterning during animal development,. Hh signal transduction leads to increased stability of a transcription factor, Cubitus interruptus (Ci),, whereas Wg signal transduction causes increased stability of Armadillo (Arm/β-catenin), a possible co-factor for thetranscriptional regulator Lef1/TCF. Here we describe a new gene, slimb (for supernumerary limbs), which negatively regulates both of these signal transduction pathways. Loss of function of slimb results in a cell-autonomous accumulation of high levels of both Ci and Arm, and the ectopic expression of both Hh⁻ and Wg⁻ responsive genes. The slimb gene encodes a conserved F-box/WD40-repeat protein related to Cdc4p, a protein in budding yeast that targets cell-cycle regulators for degradation by the ubiquitin/proteasome pathway^,,. We propose that Slimb protein normally targets Ci and Arm for processing or degradation by the ubiquitin/proteasomepathway, and that Hh and Wg regulate gene expression at least in part by inducing changes in Ci and Arm, which protect them from Slimb-mediated proteolysis.