The universal education movement has dramatically increased the number of children attending primary school in Africa and Asia. Progress is now sorely needed at the secondary level. Children are unable to enter and complete secondary school given a daunting array of socioeconomic, cultural, and logistical barriers. Those who manage to overcome these barriers and attend secondary school are still held back—by outdated curricula and pedagogies that offer inadequate preparation for the 21st century marketplace. To help address these challenges, a group of donors collaborate in grant making through the Partnership to Strengthen Innovation and Practice in Secondary Education (PSIPSE). Together, they aim to support the development and testing of innovative models to address barriers to achievement in secondary education, facilitate the scale-up of effective interventions in its target countries, and promote efforts to expand the evidence base. Between 2012 and 2016, the PSIPSE committed almost $50 million to support grantees in the Democratic Republic of Congo (DRC), India, Kenya, Malawi, Nigeria, Rwanda, Tanzania, and Uganda. Mathematica Policy Research started working with the PSIPSE in late 2014 as its learning partner. In this brief, we share our analysis of the PSIPSE approach to effecting change in secondary education—starting with the partnership’s theory of change, countries of focus, and interventions supported. We end by presenting the monitoring, evaluation, and learning (MEL) framework developed for the PSIPSE and distilling some implications of our analysis for the future.