The unique nature of body handedness, which is distinct from the anteroposterior and dorsoventral polarities, has been attracting growing interest in diverse biological disciplines. Recent research progress on the left-right asymmetry of animal development has focused new attention on the mechanisms underlying the development and evolution of invertebrate handedness. This exploratory review of currently available information illuminates the prospective value of Drosophila and pulmonate snails for innovative new research aimed at elucidating these mechanisms. For example, findings in Drosophila and snails suggest that an actin filament–dependent mechanism may be evolutionarily conserved in protostomes. The polarity conservation of primary asymmetry across most metazoan phyla, which visceral handedness represents, indicates developmental constraint and purifying selection as possible but unexplored mechanisms. Comparative studies using Drosophila and snails, which have the great advantages of using genetic and evolutionary approaches, will accelerate our understanding of the mechanisms governing the conservation and diversity of animal handedness. Developmental Dynamics 237:3497–3515, 2008. © 2008 Wiley-Liss, Inc.