One of the most difficult tasks in forensic medicine is deciding the cause of death in an unclear or debatable case. Most decision-making difficulties arise when there is a definite or potential causal interaction between: disease, injury, and circumstantial events. Sometimes these interactions are trivial, but in many instances the causal interaction is undeniably important, potentially important, or of uncertain relevance. In some cases, the cause of death may be unascertainable despite best efforts, and the pathologist must resist attempts at a presumptive, but objectively un-substantiated diagnosis. In general, there are three major categories that lead to difficulties: (i) co-existence of a pre-existing condition and a fatal injury; (ii) competing potential causes of death; (iii) historical events may be causally relevant to death by injury. In this review, these categories are discussed in detail and illustrated with relevant examples.