Early researchers studying the condensation product of carbonyl compounds with N-substituted hydroxylamines elected to coin the term “nitrone” as a combination of the words “nitrogen” and “ketone.” This was done to emphasize the parallel between this newly discovered functionality and the already rich chemistry of the carbonyl group. For example, nitrones are capable of reacting with carbanions of various types, a consequence of the iminium species embedded in the nitrone that renders the functionality susceptible to nucleophilic attack. Thus C-phenyl-N-methylnitrone undergoes a Reformatsky reaction with ethyl bromoacetate in complete analogy with benzaldehyde. The intermediate zinc alkoxide cyclizes to 2-methyl-3-phenylisoxazolidin-5-one, a type of compound that can also be prepared by the related nucleophilic addition of dialkyl malonates to nitrones. This chapter deals with a unique property of nitrones not shared by the corresponding carbonyl compounds, namely, a marked ability to undergo a [3 + 2] cycloaddition reaction in the presence of a dipolarophile. The reactions of nitrones with substituted olefins, both intermolecular and intramolecular are addressed. This process yields isoxazolidines directly, affording products related to those obtained in the Reformatsky reaction but arising by a different reaction mode. The intent of the review presented in this chapter is to provide a thorough understanding of the nitrone–olefin [3 + 2] cycloaddition reaction and to illustrate its power by describing some significant applications to complex synthetic problems. Various aspects have been reviewed. This documentation of the nitrone–olefin cycloaddition reaction begins with the preparation and stability of the nitrone component and is followed by mechanistic considerations. A presentation of the dipolarophile syntheses is beyond the scope of this chapter; however, the tabular survey provides leading references to specific examples. The important concepts of regio- and stereo-selectivities are introduced next. Since the general rules of regiochemistry that apply in the intermolecular version of the reaction are often reversed in the intramolecular version, the latter are dealt with separately. Finally, important applications to the total synthesis of natural products are presented. The versatile utility of the nitrone–olefin cycloaddition reaction in the synthesis of natural products has been the major driving force in the development of this long-neglected chemistry. An in-depth understanding of the key transformations of the isoxazolidines afforded by the reaction will place this chemistry firmly within the arsenal of organic reactions. Keywords: cycloaddition reactions; [3 + 2] reaction; nitrone; olefins; nitrone stability; mechanism; regioselectivity; intermolecular reaction; intramolecular reaction; C-alkenylnitrones; N-alkenylnitrones; natural products; alkaloids; biotin; aldehyde-derived nitrones; ketone-derived nitrones; endocyclic nitrones; exocyclic nitrones; amino glycosides; adaline; nitrogen-free systems; experimental procedures