Accurate detection of gene mutations is important in many areas of biology and medicine. In fundamental studies of mutagenesis it is often necessary to assess all possible mutations, either spontaneous or induced by genotoxic agents, in a particular gene or gene sequence to explain a given cellular or physiological endpoint. In molecular medicine comprehensive detection of all possible mutations in a disease gene is required before clinical genetic testing becomes feasible. Of the many mutation detection methods currently available none is capable of scanning for all possible mutations in a cost-effective manner. Here we show that by two-dimensional DNA electrophoretic separation, on the basis of both size and base pair sequence, in principle all mutations in a given gene can be detected. This is illustrated by some data on 2-D electrophoresis of 10 exons of the cystic fibrosis gene.