Interest in fetal origins of adverse offspring outcomes has grown extensively in the last decade. This has resulted in many published studies focusing on exposure in utero to substances and human offspring outcomes. Exposure to maternal substance use in pregnancy is believed to be a preventable hazard, and is therefore a main issue for public health concern and policy. However, an important question in human studies remains whether prenatal substance use exposure has an aetiological role in pathways to adverse developmental and behavioural outcomes via teratological effects. Recent insights and developments in research methodology will aid the adequate and more refined testing of associations between prenatal substance use and offspring outcomes. In particular, novel approaches could assist in disentangling the exposure to substance effects from correlated risk factors. The purpose of this manuscript is therefore to provide an overview of methodological issues involved in studies that focus on the association between maternal substance use during pregnancy and offspring's outcomes, to describe novel approaches to test these associations, and present some examples of new and well-designed studies and discuss their findings.