Until recently, research on (S)-(-)-nicotine (1, hereafter simply nicotine) and nicotinic acetylcholine receptors (nAChRs) emphasized two principal aspects. The first was the considerable medical and commercial interest in understanding the health consequences of smoking and the mechanisms involved with tobacco dependence.1-3 Second, the ready isolation of the nAChR from the electric organ of Torpedo ray or Electrophorus fish and the existence of snake toxins with high affinity for this receptor account for its status as the archetypal member of a superfamily of ligand gated ion channels (LGIC).4,5 Recently, more attention has been directed to the potential role of neuronal nAChRs in disease and therapy.6-13 To maximize the potential of nAChRs as therapeutic targets, the central questions are: What nAChR subtypes exist in vivo, and which are responsible for the various effects observed with nicotine, such as cognition/attention enhancement, analgesia, neuroprotection, neurotransmitter release, addiction, and seizures, and which, if any, are altered in various disease states? Can selective agonists and antagonists be developed for use as pharmacological tools and therapeutic agents? Discussion of issues relevant to these questions forms the basis of this Perspective Article.