There is growing evidence that non-communicable diseases (NCDs) are a major health and socio-economic issue in low- and middle-income countries (LMICs). According to World Health Organization (WHO) estimates, deaths from cardiovascular disease, cancer, chronic respiratory disease and diabetes accounted for 63 per cent of global mortality in 2008, of which 80 per cent was in LMICs. The NCD burden is projected to increase: by 2030, NCDs will be the greatest killer in all LMICs. Thus, governments of these countries cannot afford to overlook policies in relation to NCDs. Several cost-effective measures exist to prevent and control NCDs. These include both population-wide interventions such as tobacco control and targeted treatment for individuals at high risk. Experience from high-income countries that have been able to control NCDs shows that responses must be comprehensive and multi-sectoral, integrating health promotion, prevention and treatment strategies, and involving the community as well as the health sector. Such a multi-faceted approach requires well-functioning health systems. In the majority of LMICs, however, health systems are fragile and will need to be adapted to address NCDs appropriately, while also continuing to tackle communicable diseases. We propose that the reform of health systems can occur in a four-phased approach in four areas: building political commitment and addressing health systems constraints, developing public policies in health promotion and disease prevention, creating new service delivery models and ensuring equity in access and payments. Several policy issues will also need to be addressed, including financing of NCD programs and the broadening of concepts of health and responsibilities for health. Adapting health systems to respond to NCDs will require a change in mindset and practices in programming for health, as well as substantial financial resources. There is scope for development partners and global health initiatives to support LMICs in addressing NCDs.