The following cases highlight several important points related to the multifactorial nature of prenatal exposure. The majority of infants exposed to substances prenatally endure longtime aftereffects from multiple potentially harmful agents. Notably, prenatal exposure occurs most frequently in the context of polysubstance use rather than the use of a single substance, in addition to a variety of psychosocial stressors. Thus, it can be difficult for the practitioner to tease apart the direct effects of prenatal substance exposure from those caused by other related factors such as prematurity, low birth weight, ongoing parental substance use and mental illness, chronic psychosocial stress, marginalization, socioeconomic disadvantage, inconsistent caregiving, trauma, and neglect. Therefore, it is necessary for the practitioner to have a solid understanding of the common neurobehavioral effects of the substance(s) to which a patient has been exposed, as well as their high rates of their co-occurrence with psychosocial stressors and overlapping potential outcomes. This chapter presents two case studies which highlight the complex neuropsychiatric interaction of prenatal exposure and environmental stress in the assessment and treatment of prenatally exposed infants and children.