Mathematical learning disabilities (MLD) occur frequently in children with specific genetic disorders, like Turner syndrome, fragile X syndrome and neurofibromatosis. This review focuses on MLD in children with chromosome 22q11.2 deletion syndrome (22q11DS). This syndrome is the most common known microdeletion syndrome with a prevalence of at least 1:4000 to 1:6000 live births. Although the clinical presentation of 22q11DS is quite variable, its major characteristics include velopharyngeal abnormalities, congenital cardiac anomalies, mild facial dysmorphism and learning difficulties. Children with 22q11DS show considerable difficulties in mathematics, despite relatively normal reading performance. While fact retrieval seems to be preserved, impairments in procedural calculation and word problem solving are particularly prominent. Children with 22q11DS also have substantial difficulties in understanding and representing numerical quantities, possibly related to poor visuospatial attention, which all might stem from their underlying abnormalities in the inferior parietal cortex. This review ends with a discussion on how research on genetic disorders might aid our understanding of MLD in general.