In this chapter, we discuss research and instructional practices that promote mechanistic reasoning in undergraduate science courses. Most science educators agree that it is important to help students explain or predict how and why phenomena occur—that is, to engage in mechanistic reasoning and explanation building; however, developing instructional materials that support students’ reasoning requires considerable effort and forethought. We have conducted several studies in undergraduate chemistry education that investigate the design and use of formative assessments aimed to elicit students’ mechanistic reasoning. In these studies, students consider a range of chemical (and biochemical) phenomena as they work through scaffolded prompts designed to activate the productive ideas that help students refine and advance their knowledge frameworks. In this chapter, we discuss both the implications from theory and the methods that result in enhanced student engagement in mechanistic reasoning. In particular, we focus on building tasks using an iterative, evidence-centered design approach, which results in reliable evidence about what students know and can do.