Worldwide, smoking remains a threat to public health, causing preventable diseases and premature mortality. Cigarette smoke is a powerful inducer of DNA methylation and gene expression alterations, which have been associated with negative health consequences. Here, we review the current knowledge on smoking-related changes in DNA methylation and gene expression in human blood samples. We identified 30 studies focused on the association between active smoking, DNA methylation modifications, and gene expression alterations. Overall, we identified 1,758 genes with differentially methylated sites (DMS) and differentially expressed genes (DEG) between smokers and nonsmokers, of which 261 were detected in multiple studies (≥4). The most frequently (≥10 studies) reported genes were AHRR, GPR15, GFI1, and RARA. Functional enrichment analysis of the 261 genes identified the aryl hydrocarbon receptor repressor and T cell pathways (T helpers 1 and 2) as influenced by smoking status. These results highlight specific genes for future mechanistic and translational research that may be associated with cigarette smoke exposure and smoking-related diseases.