Homeodomain proteins are transcription factors that share a related DNA binding domain, the homeodomain. This class of proteins was first recognized in the fruitfly Drosophila melanogaster where they cause homeotic transformations such as a fly with four wings instead of two (Lewis EB. A gene complex controlling segmentation in Drosophila. Nature 1978;276:565–570 [Ref. 18]). They are now known to exist in all eukaryotes where they perform important functions during development. Given that homeodomain proteins are transcription factors, they control the expression of downstream genes to regulate development. Which genes are controlled by homeodomain proteins and how many of them are there? This review focuses on a recent paper by Liang and Biggin (Liang Z, Biggin MD. Eve and Ftz regulate a wide array of genes in blastoderm embryos: the selector homeoproteins directly or indirectly regulate most genes in Drosophila. Development 1998;125:4471–4482 [Ref. 1]), which proposes that the Drosophila homeodomain proteins Even-skipped and Fushi-tarazu directly control the expression of the majority of genes in the Drosophila genome. An alternative view, that most genes are only indirectly affected by homeodomain proteins is also discussed. BioEssays 21:267–270, 1999. © 1999 John Wiley & Sons, Inc.