Learning human anatomy may be a difficult task for students for a variety of reasons including the quantity of material in the course or discipline-specific factors such as understanding anatomical terminology or learning complex physiological processes. Additionally, students may find certain organ systems more challenging than others. While prior studies have assessed student perceptions of learning specific organ systems in a variety of settings, it is unknown what organ systems students in an undergraduate human anatomy course find most difficult to learn. The goals of this study were to determine what organ systems undergraduate human anatomy students find most and least challenging to learn and to determine the reasons why they feel as they do. The results of this study showed that students overwhelmingly found the peripheral nervous system to be the most difficult to learn because of complex structure-function relationships and their inability to visualize the system. Conversely, students thought that the cardiovascular and skeletal systems were the least challenging to learn because of prior exposure to them and ease of visualization. These findings allow for the development and alteration of instructional strategies to address the issues that students face when learning about difficult organ systems.