Biological complexity has forced scientists to develop highly reductive approaches, with an ever-increasing degree of specialization. As a consequence, research projects have become fragmented, and their results strongly dependent on the experimental context. The general research question, that originally motivated these projects, appears to have been forgotten in many highly specialized research programmes. We here investigate the prospects for use of an old regulative ideal from systems theory to describe the organization of cellular systems ‘in general’ by identifying key concepts, challenges and strategies to pursue the search for organizing principles. We argue that there is no tension between the complexity of biological systems and the search for organizing principles. On the contrary, it is the complexity of organisms and the current level of techniques and knowledge that urge us to renew the search for organizing principles in order to meet the challenges that are arise from reductive approaches in systems medicine. Reductive approaches, as important and inevitable as they are, should be complemented by an integrative strategy that de-contextualizes through abstractions, and thereby generalizes results.