The Wnt–GSK3–ß-catenin pathway is central to processes at many stages of development and is highly conserved between species (Wodarz and Nusse, 1998). It is a complex pathway with branching outputs and alternative inputs at almost every step (Arias et al., 1999) and it therefore touches on many other regulatory systems. These features of Wnt–GSK–ß-catenin signaling perhaps reflect how ancient this pathway is evolutionarily (Gerhart, 1999), allowing time for the signaling apparatus to accrete additions and variations. Its inappropriate activation is also clinically important in many cancers (Polakis et al., 1999). Glycogen synthase kinase 3 (GSK3) is a central enzyme in this pathway. It was originally identified as a serine/threonine kinase involved in the regulation of glycogen by insulin (Woodgett, 1990; Welsh and Proud, 1993) and is now implicated in many different biological processes including tumorigenesis, cell survival, and developmental patterning (Fig. 1). Some of its roles in development were recently reviewed in this journal (Ferkey and Kimelman, 2000). GSK3 is involved in a number of quite distinct signal transduction pathways with different inputs and outputs (eg, Hunter, 1997). Thus, an intriguing and important question is how cross talk between these pathways is prevented. Recent progress in studies of Wnt signaling has suggested some possible answers to this question. However, the mechanism by which Wnt actually regulates GSK3 is still unknown. In this regard, it is the questions that are just beginning to emerge.