Homeoproteins are transcription factors known to be involved in the early patterning of the nervous system and in lineage decisions. While studying a possible role for homeoproteins at later stages of neuronal differentiation, we observed that the Antennapedia homeodomain is internalized by neurons, translocated to their nuclei, and enhances neurite outgrowth. Studies with mutant homeodomains showed that neurite elongation by post-mitotic vertebrate neurons is regulated by homeoproteins. An intriguing possibility suggested by these results, is that full length homeoproteins might be able to translocate through neuronal membranes. We now report that the entire Hoxa-5 homeoprotein is taken up by fibroblasts and neurons in culture and conveyed to their nuclei. Internalization occurs at 4 and 37 degrees C, and at concentrations as low as 10 pM compatible with a physiological mechanism.