The Knotted-1 (Kn1) locus is defined by several dominant gain-of-function mutations that alter leaf development. Foci of cells along the lateral veins do not differentiate properly, but continue to divide, forming outpocketings or knots. The ligule, a fringe normally found at the junction of leaf blade and sheath, is often displaced and perpendicular to its normal position. The phenotype is manifested in all cell layers of the leaf blade, but is controlled by a subgroup of cells of the inner layer. Mutations result from the insertion of transposable elements or a tandem duplication. We show that the Kn1 gene encodes a homeodomain-containing protein, the first identified in the plant kingdom. Sequence comparisons strongly suggest that Kn1 acts as a transcription factor. Here we use the Kn1 homeobox to isolate other expressed homeobox genes in maize. The Kn1 homeobox may permit the isolation of genes that, like animal and fungal counterparts, regulate cell fate determination.