This is the final version of the article. Available from Public Library of Science via the DOI in this record.We can regard the wider incentive structures that operate across science, such as the priority given to novel findings, as an ecosystem within which scientists strive to maximise their fitness (i.e., publication record and career success). Here, we develop an optimality model that predicts the most rational research strategy, in terms of the proportion of research effort spent on seeking novel results rather than on confirmatory studies, and the amount of research effort per exploratory study. We show that, for parameter values derived from the scientific literature, researchers acting to maximise their fitness should spend most of their effort seeking novel results and conduct small studies that have only 10%-40% statistical power. As a result, half of the studies they publish will report erroneous conclusions. Current incentive structures are in conflict with maximising the scientific value of research; we suggest ways that the scientific ecosystem could be improved.Funding: Medical Research Council and the University of Bristol (grant number MC_UU_12013/6).Received by MRM. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Natural Environment Research Council (grant number NE/L011921/1).Received by ADH. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. MRM is a member of the UK Centre for Tobacco and Alcohol Studies, a UKCRC Public Health Research: Centre of Excellence. Funding from British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, and the National Institute for Health Research, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged