Sub-Saharan Africa is facing an expected doubling of human population and tripling of food demand over the next quarter century, posing a range of severe environmental, political, and socio-economic challenges. In some cases, key Sustainable Development Goals (SDGs) are in direct conflict, raising difficult policy and funding decisions, particularly in relation to trade-offs between food production, social inequality, and ecosystem health. Here we use a horizon-scanning approach to identify 100 practical or research-focused questions that, if answered, would have the greatest positive impact on addressing these trade-offs and ensuring future productivity and resilience of food-production systems across sub-Saharan Africa. Through direct canvassing of opinions, we obtained 1339 questions from 331 experts based in 55 countries. We then used online voting and participatory workshops to produce a final list of 100 questions divided into 12 thematic sections spanning topics from gender inequality to technological adoption and climate change. Using data on the background of respondents, we show that perspectives and priorities can vary, but are largely consistent across different professional and geographical contexts. We hope these questions provide a template for establishing new research directions and prioritising funding decisions in sub-Saharan Africa.