The mouse lines were developed by long-term selection for fatness, after which the fat line (F) had about a 5-fold (23% vs 4%) higher fat percentage than the lean (L) line at 14 weeks; but the lines differed little in fat-free body weight. To assess the contribution of genetic changes in leptin hormone level to the selection response, plasma leptin levels were assayed in these lines in generation 60 and in an unselected control (C) from the same base population. With access to food prior to assay, the F, C and L lines had 16·5, 0·91 and 0·26 ng/ml leptin, respectively. In fasted animals these levels were much lower: 2·98, 0·171 and 0·0087 ng/ml, respectively. Thus the leptin levels differ greatly between the lines, with the fattest mice showing the highest level: almost 20 times higher than the control and 60–300 times higher than the L line. These correlated selection effects are an order of magnitude greater than the direct selection response, and believed to be much larger than seen for any hormonal or other trait. Correlations between leptin level and fat amount were high (over 0·86) in fed or fasted animals of the F line, indicative of leptin resistance.