This publication introduces a series of eight other publications describing the non-clinical assessment and initial clinical study of a candidate modified risk tobacco product (MRTP) – the Tobacco Heating System 2.2 (THS2.2). This paper presents background information on tobacco harm reduction, to complement the approaches of increasing smoking cessation and reducing smoking initiation to reduce the morbidity and mortality caused by cigarette smoking. THS2.2 heats tobacco without combustion, and the subsequent formation of harmful and potentially harmful constituents (HPHC) is greatly reduced compared with cigarette smoke. Assessment of the THS2.2 aerosol in vitro and in vivo reveals reduced toxicity and no new hazards. Additional mechanistic endpoints, measured as part of in vivo studies, confirmed reduced impact on smoking-related disease networks. The clinical study confirmed the reduced exposure to HPHCs in smokers switching to THS2.2, and the associated transcriptomic study confirmed the utility of a gene expression signature, consisting of only 11 genes tested in the blood transcriptome of subjects enrolled in the clinical study, as a complementary measure of exposure response. The potential of THS2.2 as an MRTP is demonstrated by the assessment and additional publications cited in this series.