Although biomedical knowledge is believed to be of little value in diagnosis of routine clinical cases, studies of clinical reasoning have found that physicians revert to use of basic biomedical knowledge when faced with challenging clinical problems. The current paper presents two experiments that empirically examine the role of biomedical knowledge in diagnosis of difficult cases by novice diagnosticians. Novices are taught to diagnose a series of artificial diseases using either knowledge of causal mechanisms or a list of clinical features. In Experiment 1, participants are then tested on two types of clinical challenges: (1) case summaries with irrelevant findings; (2) cases using unfamiliar terminology. Participants with an understanding of underlying mechanisms out performed their counterparts on both types of cases. In Experiment 2, participants are tested 1 week after initial training. Participants with knowledge of causal mechanisms were found to do better on cases with unfamiliar terminology. The results of the two studies provide additional support for the critical role of biomedical knowledge in diagnosis of difficult clinical cases.