Amyotrophic lateral sclerosis (ALS), the most common motor neuron (MN) disease of adults, is characterized by the degeneration of upper MNs in the motor cortex and lower MNs in the brain stem and spinal cord. Our recent work suggests that a MAP kinase family member, MAP4K4 (mitogen-activated protein kinase kinase kinase kinase 4), regulates MN degeneration in ALS. Activation of MAP4K4 occurs prior to MN death and inhibition of MAP4K4 improves neurite integrity and neuronal viability in a cell autonomous manner. The mechanism through which MAP4K4 reduction specifically modulates MN viability can be attributed to the attenuation of the c-Jun apoptotic pathway, as well as to the activation of FoxO1-mediated autophagy that reduces the accumulation of protein aggregates. We additionally show the feasibility of MAP4K4 as a drug target using a MAP4K4-specific inhibitor, which improves the survival of both primary and induced pluripotent stem cell (iPSC)-derived MNs. Our studies are thus far the first to highlight a MAP4K4-initiated signaling cascade that contributes to MN degeneration in ALS, providing a new mechanism underlying MN death in disease and a druggable target for new therapeutics. We propose exciting future directions and unexplored avenues based upon this work.