Responses to hypoxia and hyperoxia depend critically on the ability of the animal to detect changes in O2 levels. However, it has only been recently that an O2-sensing system has been identified in invertebrates. Evidence is accumulating that this molecular O2 sensor is, surprisingly, a class of soluble guanylyl cyclase (sGC) known as atypical sGCs. It has long been known that the conventional sGC alpha and beta subunits form heterodimeric enzymes that are potently activated by NO, but do not bind O2. By contrast, the Drosophila melanogaster atypical sGC subunits, Gyc-88E, Gyc-89Da and Gyc-89Db, are only slightly sensitive to NO, but are potently activated under hypoxic conditions. Here we review evidence that suggests that the atypical sGCs can function as molecular O2 sensors mediating behavioral responses to hypoxia. Sequence comparisons of other predicted O2-sensitive sGCs suggest that most, if not all, insects express two heterodimeric sGCs; an NO-sensitive isoform and a separate O2-sensitive isoform. Expression data and recent experiments that block the function of cells that express the atypical sGCs and experiments that reduce the cGMP levels in these cells also suggest a role in behavioral responses to sweet tastants.