Cigarette smoke alters the transcriptome of multiple tissues; those directly exposed to toxic products and those exposed to circulating components and metabolic products of tobacco smoke. In most tissues and organs that have been studied, the smoking transcriptome is characterized by increased expression of antioxidant and xenobiotic genes as well as a wide spectrum of inflammation-related genes, and potential oncogenic genes. Smoking is associated with an increased incidence of cancer in a number of organs both those directly exposed (lungs and airways) and those indirectly exposed (bladder, liver, pancreas). Individual transcriptomic responses vary, based to some degree on as yet to be clarified genetic factors, and likely how and what the individual has smoked. The complexity of individual responses to tobacco exposure and of smoking-related cancers in various organs is beginning to be revealed in transcriptomic and whole genome sequencing studies, of both tumors and cytologically normal appearing cells that have been exposed to cigarette smoke or its products creating a genomic “field of injury.” The recent application of next generation sequencing to defining the transcriptome alterations induced by cigarette smoke holds the promise of discovering new approaches to personalized prevention and treatment of smoking-related lung diseases in the future.