The HAND subclass of basic Helix-loop-helix factors is comprised of two members HAND1 and HAND2. HAND genes are present within the genomes of organisms ranging from flies to man. Experiments employing chick embryology, tissue culture, and gene targeting in mice show that HAND function is critical for the specification and/or differentiation of extraembryonic structures that include the yolk sac, placenta, and the cells of the trophoblast lineages. HAND factors also play key roles in cardiac, gut, sympathetic neuronal development and in the proper development of tissues populated by HAND-expressing neural crest cells, including regions of the developing vasculature, the limbs, the jaw, and teeth. Surprisingly, nearly 10 years after their initial identification and characterization, little is understood about the nature of the downstream target genes which HAND1 and HAND2 regulate, whether the nature of their transcriptional regulation is positive or negative, or if they modulate genetic programs common to these diverse tissue types or if they drive unique subsets of genes that contribute to tissue identity. At the core of these questions is by which mechanisms do HAND factors modulate biological activity? Do they behave like classical class B bHLH factors or is their function more complex requiring a rethinking of the dogma? What follows is a review of what is currently known about HAND factors and a reflection on why elucidating their role in the biological programs within which they participate has been so difficult.