Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease mainly affecting motor neurons in the motor cortex, brainstem, and spinal cord. The degeneration and loss of motor neurons cause denervation at the neuromuscular junction that, in turn, lead to paralysis and death. About 90–95% of ALS cases are sporadic (sALS), while 5–10% of cases have a familial history (fALS). sALS and fALS share several features, including protein aggregation, motor neuron hyperexcitability, trafficking defects, disruption of nucleocytoplasmic transport, oxidative stress, mitochondrial dysfunction, glutamate excitotoxicity, and neuroinflammation. Specifically, oxidative stress, mitochondrial dysfunction and neuroinflammation are the primary focus of this chapter as they are all closely related to NADPH oxidase function. Finally, we discuss therapeutic strategies aimed at decreasing oxidative stress and neuroinflammation in ALS.