This paper reviews the currently available information on naturally occurring Mendelian diseases in man; it is aimed at providing a background and framework for discussion of experimental data on radiation-induced mutations (papers II and III) and for the estimation of the risk of Mendelian disease in human populations exposed to ionizing radiation (paper IV). Current consensus estimates indicate that a total of about 125 per 10 4 livebirths are directly affected by one or another naturally occurring Mendelian disease (autosomal dominants, 95/10 4; X-linked ones, 5/10 4; and autosomal recessives, 25/10 4). These estimates are conservative and take into account conditions which are very rare and for which prevalence estimates are unavailable. Most, although not all, of the recognized “common” dominants have onset in adult ages while most sex-linked and autosomal recessives have onset at birth or in childhood. Autosomal dominant and X-linked diseases (i.e., the responsible mutant alleles) presumed to be maintained in the population due to a balance between mutation and selection are the ones which may be expected to increase in frequency as a result of radiation exposures. Viewed from this standpoint, the above assumption seems safe only for a small proportion of such diseases; for the remainder, there is no easy way to discriminate between different mechanisms that may be responsible or to rigorously exclude some in favor of some others. Mutations in genes that code for enzymic proteins are more often recessive in contrast to those that code for non-enzymic proteins, which are more often dominant. At the molecular level, with recessives, a wide variety of changes is possible and these include specific types of point mutations, small and large intragenic deletions, multilocus deletions and rearrangements. In the case of dominants, however, the kinds of recoverable point mutations and deletion-type changes are less extensive because of functional constraints. The mutational potential of genes varies, depending on the gene, its size, sequence content and arrangement, location and its normal functions, and can be grouped into three groups: those in which only point mutations have been found to occur, those in which only deletions or other gross changes have been recovered and those in which both kinds of changes are known. Molecular data are available for about 75 Mendelian conditions and these suggest that in approximately 50% of them, the changes categorized to date are point mutations and in the remainder, intragenic deletions or other gross changes; there does not seem to be any fundamental difference between dominants and recessives with respect to the underlying molecular defect. Onset age for Mendelian diseases appears related to the normal function disrupted or abolished by the mutation and not necessarily to the underlying molecular change. Point mutations do not appear to be distributed at random throughout the gene; CpG dinucleotide sequences, when present in the gene, provide “hot-spots” for transition-type mutations, but not all transitions occur at CpG sequences. The breakpoints involved in intragenic deletions also are not distributed at random within the gene. In cases analyzed, the length of the deletion per se is not correlated with the severity of the clinical effect. The data from a number of well-analyzed gene deletions are consistent with mechanisms that assume base mispairing between repeat sequences and slippage during replication, homologous unequal recombination between evolutionarily related genes, homologous unequal recombination between repetitive sequences such as Alu and non-homologous recombination. Not all deletions involve Alu sequences. There is circumstantial evidence supporting the hypothesis that repetitive sequences may play an important role in chromosome pairing; if true, the deletions and duplications that have been found to be associated with some diseases may represent the inevitable by-products of occasional mispairing.