The MAP3K dual-leucine zipper kinases are stress-sensing signaling molecules that have important roles in neuronal development and maintenance, traumatic injury, and neurodegeneration. These kinases activate signal transduction cascades and elicit distinct cellular phenotypes in response to a variety of physiological and pathological stimuli. Studies from animal and cellular models have supported their conserved functions and also highlight context and cell-type specificity. This review focuses on recent findings on the molecular landscape associated with these kinases and discusses key themes of the DLK function network in the mammalian nervous system.