Fluorine-containing cyclopropanes are a subclass of cyclopropane derivatives that have generated considerable interest in medicinal chemistry for several decades. The replacement of a cyclopropane C-H or C-CH3 bond with fluorine or a fluorinated group (such as CF3 or CF2H) can lead sometimes to synergistic effects in terms of biological activity and improved metabolic profile of a cyclopropane containing bioactive compound. In this context, the preparation of fluoro-, difluoromethyl-, or trifluoromethyl-cyclopropane is particularly attractive and important but quite challenging considering the unique electronic properties that result from the incorporation of a fluorine atom into a substrate or a reagent. In the past decade, we have sought to develop new routes for the stereoselective synthesis of these building blocks using the most reliable cyclopropanation methods and convenient and readily available starting materials. The challenge that had to be undertaken was how we could use the unique properties of the fluorine atom to improve upon the efficiency of a given process rather than shutting it down. This could be overcome by defining new substrate/reagent reactivity guidelines and carefully selecting whether the fluorinated group was introduced on the electrophilic or nucleophilic partner for a given reaction. In this Account, we describe our contributions in this area that take advantage of diazo-derived rhodium carbenes, zinc carbenoids, ring closure processes, and biocatalytic methods to access these important potential drug subunits. Our initial investigation relied on the development of a Michael-initiated ring closure reaction using the Reformatsky enolate derived from readily available ethyl dibromofluoroacetate and α,β-unsaturated electrophiles. The reaction proceeded extremely well but with modest to good diastereoselectivities with ester acrylates. Further extension to various fluorinated nucleophiles such as oxazolidinone based and DABCO ylides led to similar selectivities.In order to access enantioenriched fluorocyclopropanes, we then investigated the chiral dioxaborolane mediated zinc carbenoid based approaches using the fluoroiodomethylzinc carbenoid/allylic alcohol combination or the iodomethylzinc carbenoid/fluoroallylic alcohol combination. Quite surprisingly, both approaches were equally successful at providing the corresponding fluorocyclopropanes with excellent diastereo- and enantioselectivities.To broaden the scope of fluorinated cyclopropane building blocks that could be prepared with good enantiocontrol, we then investigated the rhodium-catalyzed cyclopropanation of fluoro-, difluoromethyl-, and trifluoromethyl-substituted alkenes with acceptor-acceptor and donor-acceptor diazo reagents. Depending on the substrate/reagent combination, Hashimoto's Rh2((S)-TCPTTL)4 or Davies' Rh2((S)-BTPCP)4 catalyst proved be the most efficient catalysts providing the cyclopropane derivatives with the highest enantioselectivities.More recently, a collaboration with Fasan's group led to the use of engineered myoglobins to catalyze the reaction of ethyl diazoacetate and difluoromethyl-substituted alkenes. This biocatalyzed process led to high turnover number and high enantioselectivities.Although our work has significantly increased the number of tools in the organic chemist's toolbox, continuous efforts in this area would be beneficial to the development of diastereo- and enantioselective approaches to allow the preparation of any elusive isomers of these valuable chiral building blocks.