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.