pathDIP is an annotated database of signaling cascades in human and non-human organisms, comprising core pathways from major curated pathways databases, and pathways predicted based on orthology, and by using physical protein interactions. Data integration and predictions increase coverage of pathway annotations for human proteome to 92%. pathDIP annotates 122,131 unique proteins in 6,401 pathways in 17 organisms (including 18,454 human proteins), annotates 36,216 pathway orphans (including 5,366 human proteins), and provides multiple query, analysis and output options.