Despite the clinical importance of trisomy 21, we have been ignorant of the causes of meiotic nondisjunction of chromosome 21. Recently, however, genetic mapping studies of trisomy 21 families have led to the identification of the first molecular correlate of human nondisjunction; i.e. altered levels and positioning of meiotic recombinational events. Specifically, increases in 0 exchange events or in distal-only or pericentromeric exchanges are significantly increased in trisomy 21-generating meioses. These observations have led to the idea that chromosome 21 nondisjunction requires 'two hits': first, the establishment in prophase I of a 'vulnerable' bivalent and second, abnormal processing of the bivalent at metaphase I or II.