Accumulation of misfolded and abnormal proteins generates probably a common and complex pathomechanism in various neurodegenerative diseases (Alzheimer’s, Parkinson’s, Huntington’s, Amyotrophic Lateral Sclerosis, and Prion) and in aging. In amyotrophic lateral sclerosis (ALS), neuroinflammation appears in the form of T-lymphocyte infiltration, presence of reactive astroglial and microglial cells. Most likely, end stage of this toxic cascade results in death of motor neurons in the cortex, brainstem, and spinal cord. More than 10 different genetic causes of familial ALS are known; but still it is a challenge to prevent the loss of descending motor tracts by suppressing the degeneration of motor neurons. This chapter will focus on the precise understanding of neuroinflammatory responses in molecular pathomechanism of ALS and it also discusses new potential therapeutic strategies to improve neuroprotection and to alleviate proteotoxicity in ALS linked motor neurodegeneration. © Springer Science+Business Media Singapore 2016.