There is overwhelming evidence that the use of tobacco products plays a major role in the pathogenesis of lung and oral cancers, cardiovascular disease, COPD, and a variety of other human diseases. In the absence of complete elimination of their use, a viable alternative is the development of tobacco products that deliver reduced levels of harmful constituents to the human body. Successful strategies aimed at harm reduction through the manipulation of tobacco leaf chemistry and composition require a detailed understanding of the cellular processes that control plant development, and the biosynthesis and accumulation of cell components and secondary metabolites that contribute to, the formation of known harm components. Our studies aim to define the signaling components and transcription factors (TFs) controlling the formation of nicotine, the most prevalent alkaloid found in cultivated tobacco (Nicotiana tobaccum L.), nornicotine, and various minor alkaloids (e.g., anatabine, anabasine, anatalline) that contribute to the production of tobacco specific nitrosamines (TSNAs) during curing and fermentation. Using genomic and transcriptomic sequence data, bioinformatics, and transgenic technologies (ectopic overexpression /RNAi knockdowns) in cultured cells and whole plants we are unraveling the transcriptional circuitry that controls alkaloid formation in response to various developmental, phytohormonal, and environmental cues. We have identified several classes of TFs that directly control expression of genes encoding key enzymes in nicotine synthesis in the response to jasmonates (JAs) and shown that directed manipulation of these TFs and their target genes can substantially alter alkaloid synthesis and accumulation. Using oligonucleotide arrays we have carried out extensive global gene expression analysis to identify novel cellular targets controlling alkaloid biosynthesis and derivation and other characteristics of leaf chemistry and composition important in harm reduction. Our progress towards harm reduced products will be discussed.