In order to untangle the biological complexity of major non-communicable diseases, such as cancer, metabolic-cardiovascular and immune-inflammatory disorders, the application of entirely new approaches is required. Systems medicine is an emerging, interdisciplinary field of study which takes into account a patient’s particular condition (in terms of genomics, environment, etc) when analysing the complex interactions that take place within the human body. Such a holistic approach is thus well suited to research the complexities of biological and biomedical events in health and disease. Systems medicine makes use of systems biology and its capabilities to model complex networks, such as metabolic and cell signalling networks. But precision medicine goes beyond systems biology and systems medicine: precision medicine follows the personalised and targeted approach of systems medicine, while employing bioinformatic tools such as big data or bioanalytics combined with cutting-edge technologies of structure biology, molecular engineering and nanomedicine. The founding institutions of the HCEMM possess the necessary expertise on these emerging research fields, which complement and further support the three research pillars of HCEMM.