In V49, Disease pathways have been expanded to include WNT in cancer, Uptake and function of anthrax toxins, and Processing-defective Hh variants abrogate ligand secretion. Metabolism now includes Aflatoxin activation and detoxification, and Immune system covers Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon. Development has been updated with EPH-EFN signaling. New pathways under signal transduction include Repression of Wnt target genes, VEGFA-VEGFR2 signaling, and Hedgehog ligand biogenesis. Updated signal transduction modules include TCF dependent signaling in response to WNT and Degradation of beta-catenin by the destruction complex. Mismatch Repair has beed added to DNA repair and Chromatin organization has been expanded to cover HDACs deacetylate histones, RMTs methylate histone arginines, and HDMs demethylate histones. Akira Kikuchi is our external author. Kurt Ballmer, Philipp Berger, Michael Edelbrock, Ernesto Guccione, Richard Hopkinson, Nancy Ip, Stephen Leppla, Shihui Liu, Yulu Liu, Anna Maria Masci, Mahtab Moayeri, Nishani Rajakulendran, Sima Salahshor, Christopher Schofield, Benjamin E Turk, Louise Walport, Michael Welsh, Jim Woodgett, and Xiang-Jiao Yang are our external reviewers.