The pioneering work of Jean Dausset on the HLA system established several principles that were later reflected in the Human Genome Project and contributed to the foundations of predictive, preventive, personalized and participatory (P4) medicine. To effectively develop systems medicine, we should take advantage of the lessons of the HLA saga, emphasizing the importance of exploring a fascinating but mysterious biology, now using systems principles, pioneering new technology developments and creating shared biological and information resources.