How do some neurons survive a lifetime while others succumb to neurodegeneration? Answering this fundamental question will be critical for treating and preventing neurodegenerative diseases. Yet to answer it we first need to understand what governs neuronal survival and how cellular stresses interfere with survival mechanisms. To do this, we study the molecular pathways that promote neuronal survival with a particular focus on the survival of axons. We use a range of molecular, genetic, biochemical, and imaging techniques to define pathways that suppress cell death and maintain metabolic support. We then ask how stresses—including misfolded proteins, physical injury, and inflammation—disrupt these survival pathways to promote neurodegeneration. Our ultimate goal is to define how a neuron reacts to its environment and how environmental stimuli affect the balance between survival and death. This approach will allow us to understand how neurodegeneration occurs and to identify novel therapeutic targets.