Neurotoxins represent unique chemical tools, pro- viding a means to 1) gain insight into cellular mech- anisms of apopotosis and necrosis, 2) achieve a morphological template for studies otherwise unat- tainable, 3) specifically produce a singular pheno- type of denervation, and 4) provide the starting point to delve into processes and mechanisms of nerve regeneration and sprouting. There are many other notable uses of neurotoxins in neuroscience research, and ever more being discovered each year. The objective of this review paper is to high- light the broad areas of neuroscience in which neu- rotoxins and neurotoxicity mechanism come into play. This shifts the focus away from neurotoxins per se, and onto the major problems under study today. Neurotoxins broadly defined are used to explore neurodegenerative disorders, psychiatric disorders and substance use disorders. Neurotoxic mechanisms relating to protein aggregates are indigenous to Alzheimer disease, Parkinson's dis- ease. NeuroAIDS is a disorder in which microglia and macrophages have enormous import. The gap between the immune system and nervous system has been bridged, as neuroinflammation is now considered to be part of the neurodegenerative process. Related mechanisms now arise in the process of neurogenesis. Accordingly, the entire spectrum of neuroscience is within the purview of neurotoxins and neurotoxicity mechanisms. Highlights on discoveries in the areas noted, and on selective neurotoxins, are included, mainly from the past 2 to 3 years. Keywords: Neurodegenerative disorders; Psychiatric disor- ders; Substance use disorders; NeuroAIDs; Protein aggre- gates; Neurotoxins; Neuroprotectants; Neurogenesis; DT- Diaphorase; Amphetamines; Salsolinol; Domoic acid; 5,7- Dihydroxytryptamine; 3-Nitropropionic acid; MPTP; 6- Hydroxydopamine; Rotenone; Paraquat INTRODUCTION: Neurotoxins and Neurotoxicity NEUROTOXINS: Gene-Environmental Interplay in Psychiatric Disorders NEUROTOXINS: Gene-Environmental Interplay in Neurodegenerative Disorders NEUROTOXINS: Gene-Environmental Interplay in Substance Use Disorders Cocaine Alcohol NEUROAIDS Neuroprotective Strategies for HAD NEUROTOXIC MECHANISMS IN NEURODEGENERATIVE DISORDERS Protein Aggregates TNF-α Schwann Cells Neuroinflammation SPECIFIC NEUROTOXINS AND NEUROTOXIC SPECIES: RECENT DISCOVERIES NMDA Receptor Agonists/Antagonists Glutamate Domoic Acid 6-Hydroxydopamine Salsolinol Leukoaminochrome-o-Semiquinone Radical Dopamine MPTP/MPP + / HPP + Paraquat Rotenone Methamphetamine 5,6- and 5,7-Dihydroxytryptamines 3-Nitropropionic acid (3-NP) Organophosphorus Compounds NEUROPROTECTION Endogenous Neuroprotectants DT-Diaphorase Melatonin Exogenous Neuroprotectants NEUROGENESIS F.P. Graham Publishing Co. Neurotoxicity Research, 2006, VOL. 10(3,4). pp. 263-285 Neurotoxins and Neurotoxicity Mechanisms. An Overview. JUAN SEGURA-AGUILAR a, * and RICHARD M. KOSTRZEWA b a Programme of Molecular & Clinical Pharmacology, ICBM, Medical Faculty, University of Chile, Santiago, Chile; b Department of Pharmacology, Quillen College of Medicine, East Tennessee State Univ., Johnson City, TN 37614, USA. jsegura@med.uchile.cl (Submitted 6 December 2006; In final form 20 December 2006) *Corresponding author. E-mail: jsegura@med.uchile.cl ISSN 1029 8428 print/ ISSN 1476-3524 online. © 2006 FP Graham Publishing Co., www.NeurotoxicityResearch.com