In the last few decades, philosophy of science has increasingly focused on multilevel models and causal mechanistic explanations to account for complex biological phenomena. On the one hand, biological and biomedical works make extensive use of mechanistic concepts; on the other hand, philosophers have analyzed an increasing range of examples taken from different domains in the life sciences to test—support or criticize—the adequacy of mechanistic accounts. The article highlights some challenges in the elaboration of mechanistic explanations with a focus on (...) cancer research and neuropsychiatry. It jointly considers fields, which are usually dealt with separately, and keeps a close eye on scientific practice. The article has a twofold aim. First, it shows that identification of the explananda is a key issue when looking at dynamic processes and their implications in medical research and clinical practice. Second, it discusses the relevance of organizational accounts of mechanisms, and questions whether thorough self-sustaining mechanistic explanations can actually be provided when addressing cancer and psychiatric diseases. While acknowledging the merits of the wide ongoing debate on mechanistic models, the article challenges the mechanistic approach to explanation by discussing, in particular, explanatory and conceptual terms in the light of stances from medical cases. (shrink)