Background: Numerous studies have been conducted in which the most common forms of maternal substance use during pregnancy (smoking, drinking or using cannabis) and maternal stress during pregnancy and her offspring's developmental or behavioural outcome have been the focus of interest. These studies seem to suggest that any perturbation caused by maternal substance use or maternal stress during fetal development may have (enduring) effects on offspring behaviour. However, recent developments in research methodology used to examine these associations question whether these prenatal influences actually cause altered offspring outcomes. Aims: This review provides a short overview of previous studies in this field of research, some methodological issues particularly involved in studies that focus on the association between maternal substance use or stress during pregnancy and offspring's outcomes. Furthermore, it introduces several new approaches that have been applied recently to test these associations. Results: Studies that applied these designs to disentangle prenatal influences from associated or inherited factors consistently show an effect of prenatal substance use exposure on birth weight, but yield little evidence for causal effects on behaviour. In contrast, prenatal stress may have a causal effect on some aspects of behaviour, although only one study thus far has been able to differentiate heritable factors from environmental factors. © 2012 Informa Healthcare.