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The recent confusion concerning the relation between hormone replacement therapy and cardiovascular disease has stirred a new wave of debate about the value and future of epidemiology. Opponents of epidemiology suggest an ever-diminishing role in an age of small risks and complex diseases, yet proponents are not in consensus about how to adapt their discipline to the challenges associated with ageing societies and changing disease patterns. While epidemiology is likely to be increasingly called upon to make sense of the risks involved with these changes, wading into this era with a mindset and tools that were derived from epidemiology's ‘golden era’ of tackling major risk factors, has created more confusion than understanding. Increasingly, we need to downsize epidemiology to what is testable, measurable, and relevant, based on robust methodology and public health rationale. Applying an evolutionary perspective, that views health problems of modernity as a manifestation of the mismatch between our ancient genes and hi-tech lifestyles, can provide guidance for a 21st century research agenda.