Technological advances combined with the aging of the population bring about an increasingly growing number of patients with chronic conditions and multi-morbidity. Multi-morbidity, the co-occurrence of chronic and/or non-chronic conditions in an individual, is the norm among elderly patients, and is becoming increasingly common among younger adults. The Israeli health system, like other systems worldwide, is faced with the challenges posed by the increase in complex multi-morbidity, in an era of growing fiscal constraints, a situation that can induce financial and organizational crises. To effectively cope with such circumstances, a paradigm shift is needed. Health systems need to focus on overall morbidity burden and multi-morbidity (rather than the prevailing one disease at a time approach) and on better care integration. The Israeli health system entails many of the essential elements for addressing the challenges of integrated care, including universal health coverage and advanced health information technology systems. Yet, like other health systems, there is a need for care management support mechanisms that are more effectively tailored to meet the needs of the highly multimorbid patients. This review outlines the organizational approach required to better align care for the main customers of health care in the 21st century: patients with multi-morbidity. We focus on four domains: assessment of morbidity burden according to measures that account for the interaction and synergism amongst conditions; integration across the care continuum; enhancement of primary care and self-management support approaches; and provision of uniquely tailored care management solutions for the highest risk multi-morbid patients.