Int. J. Environ. Res. Public Health 2011, 8 1. Introduction 90 In Fallujah (Iraq), birth defects, with prevalence of congenital heart defects (CHD) and neural tube defects (NTD), have reached in 2010 unprecedented numbers, above the World average [1]. Lack of a comprehensive birth registry has made it difficult to make an accurate comparison with the pre war period and to understand modalities and dimension of this unusual occurrence in Fallujah. We thus introduced a protocol allowing for reconstruction of the reproductive history of families with birth defects in Fallujah that allows to see the pattern of their presentation in time. We present here the analysis of four cases of fathers with two lineages of progeny, chosen among more than 50 cases under study. Birth defects presented here are classified according to the primary defect as NTD (neural tube defects), CHD (cardiac birth defects), SK (skeletal defects), even when they have additional phenotypes, or O (others). Modalities of presentation within each family suggest that epigenetic factors may be at the origin of the mechanisms responsible for these defects. The timing of the birth defect occurrences suggests that they may be related to war-associated long-term exposure to contamination. The epigenetic origin of many birth defects is extensively supported by the existing literature [2]. Neural tube defects are rarely due to traceable genomic changes. The high rate of recurrence of anencephaly in siblings (6.3%) is understood as due to environmental factors and maternal effects. Studies of NTD in mice indicate that anencephaly may be due to multifactorial combinations of hypomorphs and low-penetrance heterozygotes. It is not known how many genes may contribute to anencephaly in humans. Congenital heart defects have various phenotypes and can be compounded by different cardiac- unrelated features. Approximately 30% of CHD and tetralogy of Fallot (TOF) have been shown to be associated with wide genomic rearrangements. Only in a very small fraction of the cases investigated have cohort studies detected mutations in single genes which are putatively involved (e.g., Holt-Oram syndrome). Environmental factors are implied in the induction of most CHD phenotypes, through epigenetic mechanisms. In mice, cleft lip is caused by epistatic interactions in the context of genetic maternal effects. Cleft lip and palate inheritance patterns suggest that the causes are combinations of genetic and nongenetic factors. Also in mice, synpolydactyly is linked to Hoxd13 mutations and its manifestation is dependent upon environmental factors. Tumorigenesis is a multistep process involving mutations and epigenetic changes [2]. Repeated cases of infant leukemia in families are due to genetic predisposition and epigenetic changes that can occur in-utero by epigenetic modifiers. Transplacental effector-molecules and epigenetic trans-generational mechanisms are implied in the manifestation of infant leukemia. Thus, although in teratogenesis and infant leukemia can occur through genomic rearrangements or concurrence of multiple single mutational events, they are most often described and understood to be due to pleiotropic epigenetic changes which affect more than one function, or to a combination of these three mechanisms. Many known war contaminants have the potential to interfere with normal embryonic and fetal development. The devastating reproductive health effects of dioxins (the major contaminant of Agent Orange) on the Vietnamese people is well known. Data is also accumulating on increased rates of