This fifth National Strategic Plan (NSP) for HIV, TB and STIs 2023-2028 provides the strategic framework for a multisectoral approach that is people- and community-centred to overcome these three epidemics as public health threats and social challenges. This new NSP provides a review of the burden of disease from HIV, TB and STIs, outlines some of the progress made in South Africa and discusses several challenges that need to be addressed with urgency.