Understanding the genetics of nicotine dependence can lead to targeted treatments and ultimately significantly decrease tobacco-associated morbidity and mortality. In the study of nicotine dependence, it is important to understand the behavioral progression to nicotine dependence when choosing a control group. Some researchers argue that smoking is a means of self-medicating and nicotine dependence is therefore caused by mental illness. Genome-wide association studies (GWAS) have found associations between nicotine dependence and the a5 nicotinic receptor subunit gene. This chapter postulates that there are at least two distinct biological mechanisms that alter the risk of nicotine dependence. The first biological mechanism is caused by an amino acid change in CHRNA5, in the non-synonymous SNP rs16969968. The second mechanism altering risk of nicotine dependence is through altered expression of the α5 mRNA. Associations in this region have also been found in lung disease.