This work, designed for clinicians, adopts a coordinated multidisciplinary approach to a range of topics central to complexity in medicine, with the aim of offering an integrated, unitary perspective that stands in contrast to the traditional simplification inherent in the subdivision into single specialties. It recognizes that medicine today has to face emerging issues that current knowledge cannot accommodate because the properties to be addressed do not simply equate to the sum of the properties of single components but rather are the product of interactions among them or among different environments. Examples include the interactions among genetic, environmental, pathological, psychological, and ethical aspects. This new model, represented by so-called systems medicine, entails a different approach, already reflected in, for instance, the view of cancer as a cellular ecosystem in evolution rather than a unique disease and the acknowledgment that future guidelines for cardiovascular prevention will have to consider many factors beyond blood pressure or cholesterol levels. It also recognizes the impact of other fields upon medicine, as in the crucial contributions of CERN to projects of great medical importance and of grid computing to genomics research. The Handbook of Complexity in Medicine offers stimulating insights into this new reality; it will provide readers with a tool for deepening their understanding of topics that even today remain somewhat unclear and will hopefully assist in decision making that takes into account this uncertainty.