The c-Jun amino terminal kinase (JNK) cascade leading to c-Jun phosphorylation has been implicated in the neuronal cellular response to a variety of external stimuli including free radical oxidative stress, trophic withdrawal, amyloid toxicity and activation by death domain receptor ligands. Although the exact causes of neuronal loss in neurodegenerative diseases remain unknown, it has been hypothesized that response to these environmental stresses may be contributing factors. Agents which block the JNK signaling cascade have been proposed as a therapeutic approach for preventing neuronal cell death observed in a variety of neurodegenerative diseases including Parkinsons, Huntingtons, and Alzheimers disease. The JNKs are regulated through a sequential signaling cascade by a series of upstream kinases including the mixed lineage kinases (MLKs). Herein, we review the MLK family as a therapeutic target and provide evidence with CEP-1347, the most advanced MLK inhibitor currently in clinical trails for Parkinsons disease, that intervention at the MLK point in the JNK cascade may reduce the susceptibility of neurons to degenerate.