Most vertebrate organs begin their initial formation by a common, developmentally conserved pattern of inductive tissue interactions between two tissues. The developing tooth germ is a prototype for such inductive tissue interactions and provides a powerful experimental system for elucidation of the genetic pathways involved in organogenesis. Members Msxl is required for the transmission of Bmp4 expression from dental epithelium to mesenchyme and also for Lefi expression.In addition, we consider the role of other signaling molecules in the epithelial-mesenchymal interactions leading to tooth formation, the role that transcription factors such as Msx play in the propagation of inductive signals, and the role of extracellular matrix. Last, as a unifying mechanism to explain the disparate tooth phenotypes in Msxl-and Msx2-deficient mice, we propose that later steps in tooth morphogenesis molecularly resemble those in early tooth development. )from a series of instructive and permissive cell-cell interactions (Saxen, 1977a;Wessells, 1977). The determination of the mesoderm and neural plate in vertebrate embryos is referred to as primary induction (Spemann and Mangold, 1924), and is followed by a series of secondary inductive events which further regulate embryonic organ development. Over the last decade, the application of molecular biology to problems in vertebrate development has revealed a considerable amount of information about the nature of the inductive signals which are exchanged between tissue layers during inductive tissue interactions (reviewed in Jessell and Melton, 1992;Kessler and Melton, 1994). This review focuses specifically on the genetic hierarchies which appear to operate during early tooth development, on the nature of the inductive signals which are exchanged between the dental epithelium and mesenchyme, and on the role that one particular class of transcription factors, those belonging to the Msx family of homeobox genes, plays in controlling these inductive tissue interactions. Several excellent recent reviews on tooth development are also available (Ruch, 1995;Sharpe, 1995;Thesleff et al., 1995a Thesleff et al., ,b, 1996 Thesleff and Sahlberg, 1996), and a "tooth gene expression database" is also available on the Internet (http://honeybee.helsinki.fi/toothexp).The dentition not only constitutes a major component of the mammalian craniofacial system, but also provides a powerful and potentially general model for the study of organ development. The possibility of in vitro cultivation, access to cytological and molecular studies, the clear delineation of epithelial and mesenchymal components, the easily distinguished characteristics of ameloblasts and odontoblasts, and the anteroposterior, position-dependent pattern of dentition make the devel-4