The teratogenicity of cigarette smoke has been widely researched over the past two decades, in large part due to the work of Fried et al. The current study was designed to investigate some methodological issues surrounding the investigation of the effects of maternal smoking along with other potentially teratogenic agents in pregnancy. Specifically, maternal smoking was investigated both as a covariate and with regards to its main and interactive effects on child IQ in a prospectively ascertained sample of children whose mothers reported pregnancy exposures to four classes of agents: varicella virus infection (VC), selective serotonin reuptake inhibitors (SSRIs), antiepileptic drugs (AEDs) and benzodiazepines (BZDs). Children were also included whose mothers were not exposed to one of these four agents during pregnancy. The goal of this study was not to examine the behavioral teratogenic potential of these agents or of maternal smoking. Rather, our goal was to illustrate some methodological issues in addressing the combined effects of these agents in behavioral teratology. In the analyses of all four exposures, when smoking was considered as a covariate, it was either a significant or marginally significant covariate and the exposure of interest was not significantly related to a change in IQ score. However, when maternal smoking was considered as a factor in the analyses, four different patterns emerged illustrating the potential importance of properly addressing maternal smoking in the analysis of other potential behavioral teratogens.