A low maximal oxygen consumption (VO2max) is a strong risk factor for premature mortality. Supervised endurance exercise training increases VO2max with a very wide range of effectiveness in humans. Discovering the DNA variants that contribute to this heterogeneity typically requires substantial sample-sizes. In the present study we first use RNA expression profiling to produce a molecular classifier that predicts VO2max training response. We then hypothesised that the classifier genes would harbour DNA variants that contributed to the heterogeneous VO2max response. Two independent pre-intervention RNA expression data sets were generated (n=41 gene-chips) from subjects that underwent supervised endurance training. One identified, the second blindly validated an RNA expression signature that predicted change in VO2max ('predictor genes'). The HERITAGE Family Study (n=473) was used for genotyping. We discovered a 29 RNA signature that predicted VO2max training response on a continuous scale, and these genes contained ~6 new SNPs associated with gains in VO2max in HERITAGE. Three from 4 novel HERITAGE candidate genes were confirmed as RNA predictor genes (i.e. 'reciprocal' RNA validation of a QTL genotype), enhancing the performance of the 29 RNA based predictor. Notably, RNA abundance for the predictor genes was unchanged by exercise training, supporting the idea that expression was pre-set by genetic variation. Regression analysis yielded a model where 11 SNPs explained 23% of the variance in gains in VO2max, corresponding to ~50% of the estimated genetic variance for VO2max. In conclusion, combining RNA profiling with single-gene DNA marker association analysis yields a strongly validated molecular predictor with meaningful explanatory power. VO2max responses to endurance training can be predicted by measuring a ~30 gene RNA expression signature in muscle prior to training. The general approach taken could accelerate the discovery of genetic biomarkers, sufficiently discrete for diagnostic purposes, for a range of physiological and pharmacological phenotypes in humans. Key words: aerobic capacity, personalised medicine, genotype, endurance training.