Significance Understanding dendritic cell (DC) migration during an immune response is fundamental to defining the rules that govern T cell-mediated immunity. We recently described mice deficient in the pattern recognition receptor NLRP10 (NLR family, pyrin domain containing 10) with a severe DC migration defect. Using whole-exome sequencing, we discovered that this defect was due to mutation of the guanine nucleotide exchange factor Dock8 (dedicator of cytokinesis 8). DOCK8 regulates cytoskeleton dynamics in leukocytes, and loss-of-function mutations cause an immunodeficiency syndrome. Mutations in other Dock genes have been reported in mice lacking innate immune pathways, and we now report two more lines with Dock8 mutations resulting in impaired DC migration. These results clarify the role of NLRP10 in DCs and confirm the essential function of DOCK8 in the immune system.