This article presents a framework for thinking about the key questions that need to be answered to develop new policy and program-relevant knowledge that can be used to make more informed decisions. It is a primer for administrators, policy makers and others about how to identify the knowledge they need to make decisions regarding new or existing programs. The article covers three related dimensions in evaluation: types of evaluations, key domains of inquiry and generic research questions. While the questions are generic, they can be readily adapted to any new and/or existing healthcare program evaluation. Examples of how the generic questions can be adapted to primary healthcare clinics and home care are presented.