This paper aims to analyse how to encourage science uptake, here defined as the uptake and use of scientific research products (including journal articles, scientific reports, tools, expert knowledge, etc.), in the South African context. While science uptake into implementation is a very case-and context-specific process, the authors propose that a general framework for analysis of the policy-making context in South Africa needs to be considered when analysing how to promote science uptake in specific cases. In this paper, the National Freshwater Ecosystem Priority Areas (NFEPA) project is used as an example to illustrate how to apply this framework and how science projects in South Africa can be better positioned for impact and use. The paper starts by introducing the framework for conceptualising the complex set of dynamic processes and actors that can be involved in science uptake by government in South Africa, i.e., the policy-making context. From this theoretical platform the authors analyse to what extent the NFEPA project will be able to support more effective implementation of existing environmental and water legislation. This is done by exploring the challenges that hinder the uptake of science in government departments and then offering recommendations on how to address these.