Parental genomic imprinting is the phenomenon in which the behavior of a gene is modified, depending on the sex of the transmitting parent [Peterson and Sapienza (1993): Annu Rev Genet 27:7-31]. Recent observations have revealed that the inheritance patterns, age-of-onset, severity, and etiology of certain human diseases can be explained by aberrations in the establishment or the maintenance of the imprint. Examples include the Prader-Willi, Angelman, and Beckwith-Wiedemann syndromes [Nicholls (1994): Am J Hum Genet 54:733-740], malignancy [Sapienza (1990): Biochim Biophys Acta 1072:51-61; Feinberg (1993): Nat Genet 4:110-113], and insulin-dependent diabetes mellitus (IDDM) [Julier et al. (1994) Nature 354:155-159; Bennett et al. (1995) Nat Genet 9:284-292]. We review the evidence that implicates an imprinted gene in the INS-IGF2 region of chromosome 11p15 in the etiology of IDDM (referred to as the IDDM2 locus) and show that in human fetal pancreas, INS is not imprinted, thus providing an argument against INS as the candidate gene. We also examine imprinting effects on the expression of IGF2 in components of the human immune system believed to be important in IDDM and show imprinted expression in fetal thymus as early as 15 weeks gestation. We demonstrate further that in the circulating mononuclear cells of two individuals, lectin-stimulated IGF2 transcription was biallelic, indicating relaxation of imprinting, whereas in one individual, transcription was monoallelic. Finally, we review the current available data supporting a role for insulin-like growth factor-II (IGF-II) in the immune system and, more specifically, discuss the evidence supporting a role for the IGFs in the prevention of apoptosis. These data have led us to formulate a novel hypothesis that could mechanistically explain the involvement of the IDDM2 locus in the pathogenesis of IDDM.