Abstract Nephrology emerged as autonomous discipline in the 1950s, after the publication of the landmark treatise of Homer Smith entitled The Kidney Structure and Function in Health and Disease (1951). The official foundation took place in 1961. For decades, during the collection of the critical mass of data that granted its autonomy, Nephrology investigated acid–base and electrolyte disorders. However, driven by biopsy, dialysis machines and transplantation its growth has been unstoppable in terms of journals, articles, books, meetings, number of specialists, clinical divisions, university chairs, and specialty schools. The most propulsive force has been, however, the switching of the focus from the care of dialysis patients to the >10% of the population who, in a country, suffer from silent or overt disease leading to chronic kidney disease, requiring a demanding and costly therapy consuming 2–3 % of the total health budget. Historical analysis disclosed that Nephrology as a specialty was born and nurtured in contact zones with other disciplines. These include chemistry, physics, pathology, immunology, pharmacology, genetics, engineering, pediatrics, geriatrics, oncology and cardiology and many more. However research focused on kidney disease, although still lush and appealing, is felt to be stagnant. Another approach based on complexity and holism rather than on strict reductionism – indispensable to provide successful care – may better serve future needs. The potential of complexity is explored along with new techniques, Big Data, and a wider use of artificial intelligence, as well as the links with philosophy, and Systems Biology, Systems Medicine, Systems Pharmacology.