The existing literature on Problem-based learning (PBL) mostly paints a positive picture. If there were more evidence of the limitations of PBL, more could be done to apply the appropriate interventions to optimize the experience of PBL for students. The purpose of this article is to discuss second year medical students' perceptions of the difficulties they face in knowledge acquisition in Biochemistry, Physiology and Anatomy during the first two years of transition from traditional education approaches to PBL. The main findings of the empirical study were that, through PBL, knowledge acquisition in Biochemistry and Physiology were perceived to be more difficult than in Anatomy. It is for this reason that, when transforming to PBL, measures need to be in place to address the challenges students might experience in acquiring knowledge in subjects like Biochemistry and Physiology.