Internal medicine patients are mostly elderly; they have multiple co-morbidities, which are usually chronic, rather than self-limiting or acute diseases. Neither administrative indicators nor co-morbidity indexes, though validated in elderly patients, are able to completely define these "complex" patients or to allow physicians to correctly "cope" with them. For the complex patients found in internal medicine wards, internists need not only to find the best diagnosis and treatment, but also to apply a complex intervention (i.e., a comprehensive assessment and both continuous and multi-disciplinary care) in order to maintain their health and ability to function and to prevent or delay disability, frailty, and displacement from home and community. The aim of this review is to underscore the differences between the concepts of co-morbidity and complexity, to discuss instruments for their measurement, and to highlight related implications, areas of uncertainty, and the responsibilities of internists in the assessment and management of inpatients of their wards. The conclusion we come to is that it is mandatory to shift from a finance/administrative-based management system to a clinical process model (clinical governance) driven by the quality of the medical outcome and the cost of achieving that outcome. From a "complexity theory" standpoint, patient-centered care and collaboration can be seen as simple rules that guide desirable behaviors in a complex system. By exploring the real complexity of our patients, we exercise the holistic, anthropologic medicine of the person that is internal medicine.