Beckwith-Wiedemann syndrome (BWS), a human overgrowth syndrome with a complex genetic basis, is caused by alterations to chromosome 11p15, a region subject to genomic imprinting. These alterations include translocations, duplications, single gene mutations of p57KIP2, and increased expression of insulin-like growth factor 2 (IGF2). A phenotypically related X-linked overgrowth syndrome, Simpson Golabi Behmel syndrome (SGBS), is caused by alterations in glypican-3 (GPC3), a molecule that may interact with the gene products identified to be important in generating the BWS phenotype, that is, IGF2 and p57KIP2. The crucial defect in these overgrowth syndromes is likely to be an imbalance in contributions of growth-promoting genes versus growth-inhibitory genes in critical tissues at specific developmental stages. Murine models have been used to study the effects of targeted deletions of the genes p57KIP2 and GPC3, as well as overexpression of IGF2. At this time, there are still many issues which remain to be explored before we can fully understand the molecular basis of BWS and SGBS.