In the undergraduate science classroom, case study pedagogy is method that uses stories with dilemmas and/or questions to convey scientific content. Case study pedagogy shows promise as an active learning pedagogy to meet the demands of 21st century biology education initiatives; however, there is a dearth of information on how students learn with case studies in the undergraduate biology classroom. The purpose of this study was to investigate variables that impact learning with case studies (prior content and contextual knowledge, situational interest, and pedagogical strategies) and the relationships between those variables to further understand how students learn with case studies in the undergraduate biology classroom. Results show that a particular pedagogical feature, small group work, moderates the relationship between prior content knowledge and situational interest. Along with increasing their knowledge of meiosis, students who had strong positive feelings that the narrative was connected to their learning (pedagogical strategies) had higher achievement on a near transfer of knowledge item (learning) after the case study. These findings underscore the idea that case studies can be used in classrooms with stratified levels of prior content knowledge. These findings can facilitate the improvement of case study pedagogy with regard to the type and level of prior knowledge in the student population, the development of case study teaching materials, the training of faculty in case study pedagogy, and ultimately the widespread adoption of the practice.