RUNX proteins are evolutionarily well-conserved transcription factors that are involved in essential aspects of the development of metazoan animals ranging from nematodes to humans. Genetic or epigenetic defects in any one of the three RUNX proteins in humans cause severe diseases. Although much is known about the functions and signaling pathways of the RUNX proteins through the use of mammalian systems, there are still gaps in our knowledge with regard to the functions of the RUNX proteins in normal development and disease states. Recently, the nematode Caenorhabditis elegans was revealed to bear one RUNX homolog (RNT-1) and one homolog of the RUNX protein partner CBF beta/PEBP2 beta (BRO-1). The expression patterns and biological functions of RNT-1 and the manner in which it is regulated are all comparable to what has been observed for the mammalian RUNX proteins. Thus, the nematode system is a promising model system for elucidating the functions and regulation of Runt proteins. In addition, it has recently emerged that the RNT-1 protein is involved in a transforming growth factor beta signaling pathway. The bro-1 gene encoding the CBF beta homolog is exclusively expressed in the hypodermis, not in the intestine, which indicates that additional tissue-specific cofactors in the intestine might exist. The possible autoregulation of RNT-1 expression by RNT-1/BRO-1 in the hypodermal cells is also discussed.