Metals are divided into essential and non-essential metals on the basis of their requirement in the maintenance of cellular homeostasis. The essential metals play significant roles in a variety of physiological processes such as oxygen transportation, protein modification and neurotransmitter synthesis, redox reactions, immune response, cell adhesion, protein, and carbohydrate metabolism. The acute and chronic exposures of metals lead to their bioaccumulation in different organs such as bone, kidney, and brain. However, excessive accumulation of metal in the system leads to oxidative stress, mitochondrial dysfunction, and impairment in the activity of various enzymes, protein misfolding, endoplasmic reticulum stress, autophagy, dysregulation, and activation of apoptosis. Epidemiological and clinical studies provided a strong provided a strong evidence on neuronal damage caused by metal accumulation in the brain which results in several neurological disorders such as Alzheimer’s disease (AD),amyotrophic lateral sclerosis (ALS),autism spectrum disorders (ASDs), Guillain–Barre disease (GBD),Gulf War syndrome (GWS),Huntington’s disease (HD),Parkinson’s disease (PD), and Wilson’s disease (WD). The growing urbanization and increasing life expectancy of population, in general, increase the incidences of metal-induced neurotoxicity. This chapter discusses the effects of various essential and non-essential metals inducing neurotoxicity and neurodegeneration leading to neurological diseases and challenges in the development of target-specific therapeutic for metal poisoning.