Like yin and yang, novelty and familiarity are typically described as separate-yet-complementary aspects of an experience, two ends of a single continuum. However, novelty and familiarity are also multifaceted. For instance, novelty can sometimes result in enhanced mnemonic performance, whereas at other times familiarity is better remembered. As previous investigations focused primarily on the experimental aspect of novelty, the mechanisms supporting conceptual novelty (the novel combination of two previously unrelated existing concepts) remain unclear. Importantly, conceptual novelty can be recognized as such only when compared with preexperimental familiar knowledge, regardless of experimental status. Here we applied a combined repetition suppression/subsequent memory fMRI paradigm, focusing on the conceptual aspect of novelty and familiarity as the subject matter. Conceptual novelty was characterized by sustained neural activity; familiarity, on the other hand, exhibited repetition effects in multiple cortical regions, a subset of which was modulated by successful encoding. Subsequent memory of novelty was associated only with activation differences in a distinct set of regions, including the hippocampus and medial cortical regions. These results suggest that conceptual novelty (a) does not (easily) trigger the repetition suppression phenomenon but requires sustained neural recruitment and (b) activates dedicated encoding mechanisms. Conceptual familiarity, in contrast, allows rapid neural processing that depends upon existing neural representations. Overall, these findings challenge the definition of novelty as a unitary concept. Furthermore, they bear important implications for research into the neural bases of knowledge representation and recognition memory.