Effective and resource-efficient long-term management of multimorbidity is one of the greatest health-related challenges facing patients, health professionals, and society more broadly. The purpose of this review was to provide a synthesis of literature examining multimorbidity and resource utilization, including implications for cost-effectiveness estimates and resource allocation decision making. In summary, previous literature has reported substantially greater, near exponential, increases in health care costs and resource utilization when additional chronic comorbid conditions are present. Increased health care costs have been linked to elevated rates of primary care and specialist physician occasions of service, medication use, emergency department presentations, and hospital admissions (both frequency of admissions and bed days occupied). There is currently a paucity of cost-effectiveness information for chronic disease interventions originating from patient samples with multimorbidity. The scarcity of robust economic evaluations in the field represents a considerable challenge for resource allocation decision making intended to reduce the burden of multimorbidity in resource-constrained health care systems. Nonetheless, the few cost-effectiveness studies that are available provide valuable insight into the potential positive and cost-effective impact that interventions may have among patients with multiple comorbidities. These studies also highlight some of the pragmatic and methodological challenges underlying the conduct of economic evaluations among people who may have advanced age, frailty, and disadvantageous socioeconomic circumstances, and where long-term follow-up may be required to directly observe sustained and measurable health and quality of life benefits. Research in the field has indicated that the impact of multimorbidity on health care costs and resources will likely differ across health systems, regions, disease combinations, and person-specific factors (including social disadvantage and age), which represent important considerations for health service planning. Important priorities for research include economic evaluations of interventions, services, or health system approaches that can remediate the burden of multimorbidity in safe and cost-effective ways.