In Drosophila, the canonical Toll signaling pathway is initiated by the binding of a spatzle ligand to Toll (Tl) or a Toll-like receptor leading to the nuclear localization of the NF-κB (dl or Dif) transcription factor. Activation of the pathway is controlled by the generation of a cleaved, active, Toll-binding form of spatzle ligand. Proteolytic activation of spatzle ligand lies downstream of several zymogen activation cascades that are initiated by different cues. The canonical Toll pathway is best characterised in the establishment of embryonic dorsal-ventral pattern and innate immunity. In dorsal-ventral patterning, localized activation of spz results in ventral nuclear accumulation of dl. During gram-positive bacterial, viral and fungal immune challenge, a zymogen cascase is activated by extracellular pattern recognition receptors or virulence factor-mediated cleavage of the zymogen persephone (psh). (Adapted from FBrf0091014 and FBrf0223077).