Globally, approximately one in three of all adults suffer from multiple chronic conditions (MCCs). This review provides a comprehensive overview of the resulting epidemiological, economic and patient burden. There is no agreed taxonomy for MCCs, with several terms used interchangeably and no agreed definition, resulting in up to three-fold variation in prevalence rates: from 16% to 58% in UK studies, 26% in US studies and 9.4% in Urban South Asians. Certain conditions cluster together more frequently than expected, with associations of up to three-fold, e.g. depression associated with stroke and with Alzheimer’s disease, and communicable conditions such as TB and HIV/AIDS associated with diabetes and CVD, respectively. Clusters are important as they may be highly amenable to large improvements in health and cost outcomes through relatively simple shifts in healthcare delivery. Healthcare expenditures greatly increase, sometimes exponentially, with each additional chronic condition with greater specialist physician access, emergency department presentations and hospital admissions. The patient burden includes a deterioration of quality of life, out of pocket expenses, medication adherence, inability to work, symptom control and a high toll on carers. This high burden from MCCs is further projected to increase. Recommendations for interventions include reaching consensus on the taxonomy of MCC, greater emphasis on MCCs research, primary prevention to achieve compression of morbidity, a shift of health systems and policies towards a multiple-condition framework, changes in healthcare payment mechanisms to facilitate this change and shifts in health and epidemiological databases to include MCCs.