A common assumption is that cardiorespiratory fitness (CRF), as evaluated by the measurement of VO2max, and cardiometabolomic risk factors improve as a result of exposure to aerobic exercise programs. Up until recently, this was considered to apply to all adult males and females. However, in a series of studies in which the exercise prescription was rigorously standardized, it was consistently observed that there are young, middle-aged and older adults who experienced little to no increase in CRF or in the risk factor profile. It is therefore of great importance for exercise medicine to understand the biological basis for the large individual differences in the trainability of CRF and the variability in responsiveness of cardiometabolomic risk factors. In this regard, exercise training studies performed in pairs of monozygotic twins and a cohort of about 200 nuclear families have revealed that CRF trainability was characterized by a heritable component of the order of 45%. In contrast, the heritability of the risk factor trait responses is heterogeneous and ranges from 20% to 50%. These low to moderate genetic components sugests that it may not be feasible to generate powerful predictive algorithms based on DNA sequence variants alone. Attempts based on a combination of single nucleotide polymorphisms and skeletal muscle gene expression profiling have been reported and have led to disgnostic improvements. However, these studies have typically been hindered by low statistical power and lack of adequate replication material. Diagnostics aimed at predicting the level of responsiveness to regular exercise must met stringent sensitivity and specificity standards and achieve a high level of predictive power in order to be of sufficient quality for applications in a personalized exercise medicine context. This is unlikely to be attained without a comprehensive approach to diagnostic development that incorporates information on personal characteristics, morphological and physiological traits, genomics, epigenomics, transcriptomics and metabolomics. Bioinformatics explorations of the signals generated in early genomic studies have yielded a number of pathways and networks that contribute to variation in CRF trainability but also reveal that it will be a challenge to develop powerful diagnostics. For instance, genes with allelic variations contributing to CRF trainability are enriched in developmental, regulation of gene expression, angiogenesis, skeletal and cardiac muscle growth, and apoptosis pathways. Based on our study of the variation in insulin sensitivity in response to regular endurance execise, one can predict that many other key pathways will emerge when the biology of the changes in cardiometabolomic risk factor traits has been more thoroughly investigated. The global topic of predicting the response the responsiveness to endurance exercise (and resistance exercise as well) is one that will benefit greatly from the science being pursued by the large NIH-funded MoTrPAC project.