Development of multicellular organisms requires precise control of transcription factor (TF) inputs into their gene regulatory networks. As such, TF activity is highly regulated, often integrating several mechanisms across multiple regulatory levels to impact developmental outcomes. In plants, this is exemplified by CLASS III HOMEODOMAIN-LEUCINE ZIPPER (HD-ZIPIII) proteins, a >650 million-year-old family that arose before the common ancestor of Chlorokybus algae and land plants. HD-ZIPIII TFs were then repeatedly coopted throughout evolution to regulate pivotal developmental innovations, including stem cell niches, lateral organs, and vasculature. HD-ZIPIII activity is regulated by multiple mechanisms, including a microRNA – mir166 – and the LITTLE ZIPPER (ZPR) family of microProteins. HD-ZIPIII proteins also contain a START domain. Initially identified in animals, START domains adopt an α/β helix-grip fold, creating a hydrophobic pocket which accommodates lipophilic ligands ranging from long-chain fatty acids to sterols to isoprenoids. Transcriptional activity of HD-ZIPIII proteins may thus be controlled by a lipid ligand, reminiscent of nuclear receptors (NRs) in mammalian systems. However, the impact of the START domain on HD-ZIPIII activity remains unknown, despite their essential roles in development and molecular identification over twenty years ago. Using PHABULOSA (PHB) as a representative HD-ZIPIII protein, we demonstrate that the START domain renders HD-ZIPIII dimers competent to bind DNA, while increasing both their frequency and transcriptional potency. Further, the effects of the START domain may be mediated by binding of a phospholipid ligand. The developmental and evolutionary implications of these findings will be discussed.