Women who are generally part of socially disadvantaged and economically marginalized groups are especially susceptible to smoking during pregnancy but smoking rates are underreported in both research and interventions. While there is evidence to support the short-term efficacy of nicotine replacement therapy (NRT) use in pregnancy, long-term abstinence rates are modest. Current health strategies and interventions designed to diminish smoking in pregnancy have adopted a simplified approach to maternal smoking—one that suggests that they have a similar degree of choice to non-pregnant smokers regarding the avoidance of risk factors, and overlooks individual predictors of non-adherence. As a result, interventions have been ineffective among this high-risk group. For this reason, this paper addresses the multiple and interacting determinants that must be considered when developing and implementing effective strategies that lead to successful smoking cessation: socioeconomic status (SES), nicotine dependence, social support, culture, mental health, and health services. Based on our review of the literature, we conclude that tailoring cessation programs for pregnant smokers may ultimately optimize NRT efficacy and reduce the prevalence of maternal smoking.