Over the years, malaria has remained the number one cause of morbidity and mortality in Tanzania. Population based studies have indicated a decline in overall malaria prevalence among under-fives from 18.1% in 2008 to 9.7% in 2012. The decline of malaria infection has occurred in all geographical zones of the country. Malaria mortality and cumulative probability of deaths have also shown a marked decline from 2000 to 2010. During the same period, area specific studies in Muheza, Korogwe, Muleba and Mvomero have also reported a similar declining trend in malaria prevalence and incidence. The decline in malaria prevalence has been observed to coincide with a decline in transmission indices including anopheline mosquito densities. The decline in malaria prevalence has been attributed to a combination of factors including improved access to effective malaria treatment with artemisinin combination therapy and protection from mosquito bites by increased availability of insecticide treated bednets and indoor residual spraying. The objective of this paper was to review the changing landscape of malaria and its implication for disease management, vector control, and livelihoods in Tanzania. It seeks to examine the links within a broad framework that considers the different pathways given the multiplicity of interactions that can produce unexpected outcomes and trade-offs. Despite the remarkable decline in malaria burden, Tanzania is faced with a number of challenges. These include the development of resistance of malaria vectors to pyrethroids, changing mosquito behaviour and livelihood activities that increase mosquito productivity and exposure to mosquito bites. In addition, there are challenges related to health systems, community perceptions, community involvement and sustainability of funding to the national malaria control programme. This review indicates that malaria remains an important and challenging disease that illustrates the interactions among ecosystems, livelihoods, and health systems. Livelihoods and several sectoral development activities including construction, water resource development and agricultural practices contribute significantly to malaria mosquito productivity and transmission. Consequently, these situations require innovative and integrative re-thinking of the strategies to prevent and control malaria. In conclusion, to accelerate and sustain malaria control in Tanzania, the prevention strategies must go hand in hand with an intersectoral participation approach that takes into account ecosystems and livelihoods that have the potential to increase or decrease malaria transmission.