Genome-wide and hypothesis-based approaches to the study of ageing and longevity have been dominated by genetic investigations. To identify essential mechanisms of a complex trait such as ageing in higher species, a holistic understanding of interacting pathways is required. More information on such interactions is expected to be obtained from global gene expression analysis if combined with genetic studies. Genetic sequence variation often provides a functional gene marker for the trait, whereas a gene expression profile may provide a quantitative biomarker representing complex cellular pathway interactions contributing to the trait. Thus far, gene expression studies have associated multiple pathways to ageing including mitochondrial electron transport and the oxidative stress response. However, most of the studies are underpowered to detect small age-changes. A systematic survey of gene expression changes as a function of age in human individuals and animal models is lacking. Well designed gene expression studies, especially at the level of biological processes, will provide hypotheses on gene–environmental interactions determining biological ageing rate. Cross-sectional studies monitoring the profile as a chronological marker of ageing must be integrated with prospective studies indicating which profiles represent biomarkers preceding and predicting physiological decline and mortality. New study designs such as the Leiden Longevity Study, including two generations of subjects from longevity families, aim to achieve these combined approaches.