The adverse effects of prenatal alcohol exposure have been documented for nearly four decades. Fetal Alcohol Syndrome (FAS) is defined by facial dysmorphology, growth deficits, and central nervous system abnormalities. A larger range of effects, including neurocognitive and behavioral dysfunction in the absence of these criteria is reflected in the non-diagnostic term Fetal Alcohol Spectrum Disorders (FASD). Understanding the neural basis of these effects is essential for treatment and intervention development. Neuroimaging studies report structural and functional abnormalities in FASD, but interpretations are complicated by co-morbid disorders and genetic influences. One influence, also linked to neurocognitive deficits and functional abnormalities, is a family history of alcoholism. Because individuals with FASD may have an underlying familial history of alcoholism, it is difficult to determine the extent to which deficits are unique to prenatal alcohol exposure. The current study used functional magnetic resonance imaging to examine BOLD response (p<.01, clusters ≥864 _l) during a task assessing memory for spatial locations relative to a vigilance condition assessing attention. Three comparisons were made: (1) children with histories of heavy prenatal alcohol exposure (ALC) vs. typically developing controls (CON); (2) ALC vs. those with no prenatal alcohol exposure, but a confirmed positive family history of alcoholism (FHP); and (3) FHP vs. CON. Fifty-four, age-matched children (18 FASD, 18 FHP, 17 CON), were selected from two ongoing neuroimaging studies examining spatial working memory (SWM). Analyses were performed using Analysis of Functional NeuroImages and SPSS. The ALC group had lower IQ, was less accurate, and showed slower response during vigilance relative to both other groups, which did not differ from each other. It was hypothesized that the ALC group would show greater BOLD response in frontal brain regions during SWM demands relative to FHP and CON youth, who would not differ from each other. In support of this hypothesis, relative to both the CON and FHP groups, the ALC group showed increased BOLD response in the left middle and superior frontal gyri during the spatial working memory condition relative to the vigilance condition (SWM contrast). Additionally, the ALC group showed unique increases in BOLD response to the SWM contrast in the left lingual gyrus and the right middle frontal gyrus in comparison to CON, and the left cuneus and precuneus in comparison to FHP. Contrary to the hypothesis, relative to CON, both ALC and FHP showed greater activation to the SWM contrast than CON in the lentiform nucleus and insular region. The FHP group showed further differences from CON in the thalamus. These results confirm previous studies suggesting SWM deficits in FASD. In addition, differences between the ALC group and the CON and FHP groups suggest the left middle and superior frontal region may be especially affected in children with FASD. Conversely, differences from the CON group in the lentiform nucleus and insular region for both the ALC and FHP groups may indicate this region is associated with family history of alcoholism rather than specifically associated with prenatal alcohol exposure.