Down syndrome (DS, Trisomy 21) and Williams syndrome (WS) are two neurodevelopmental disorders of genetic origin that are accompanied by mild to moderate intellectual disability but exhibit distinct cognitive profiles. In this review we discuss our recent work characterizing the real-world spatial learning and memory abilities of adult individuals with DS and WS. We used several different paradigms in which participants locomote freely and have access to coherent input from all sensory modalities to investigate their fundamental egocentric (body-centered or viewpoint-dependent) and allocentric (world-centered or viewpoint-independent) spatial abilities. We found unequivocal evidence that most individuals with DS exhibit low-resolution egocentric and allocentric spatial learning and memory abilities similar to typically developing (TD) children in the same mental age range. In contrast, most individuals with DS exhibit impaired high-resolution allocentric spatial learning and facilitated response learning as compared to TD children. In comparison, whereas most individuals with WS also exhibit facilitated response learning, their low-resolution allocentric spatial learning and memory abilities are severely impaired as compared to both TD children and individuals with DS. Together with work from other laboratories using real-world or virtual reality paradigms, these findings indicate that in order to navigate in their environment most individuals with DS may use either egocentric route learning that does not integrate individual landmarks, or a low-resolution allocentric spatial representation that encodes the relationships between different locations (i.e., cognitive mapping). In contrast, since most individuals with WS are unable to build or use a low-resolution allocentric or configural representation of the environment they may use visually and verbally encoded landmarks as beacons to learn routes. Finally, we discuss the main neural structures implicated in these different spatial processes and explain how the relative preservation or impairment of specific brain functions may engender the unique cognitive profiles observed in individuals with these neurodevelopmental disorders.