ABSTRACT The current research was an investigation of the effects of prior, domain-relevant knowledge on self-derivation of new, integrated knowledge. Adults were presented with novel “stem” facts and tested for self-derivation of new knowledge through integration of the facts in memory. To examine the effects of prior knowledge on memory integration, we tested participants under three within-subject conditions, in which in advance of stem encoding, they were provided with either: (1) no domain relevant information (No Knowledge control), (2) generally relevant information about the domain (General), or (3) generally relevant information about the domain along with a stem fact that was directly necessary for self-derivation (General + Stem). Prior exposure to both General and General + Stem knowledge facilitated memory for the novel, explicitly-taught stem facts. Moreover, for both prior knowledge conditions, the amount of domain-relevant knowledge retained in memory was associated with trial-by-trial self-derivation success. Importantly, the type of prior knowledge modulated memory integration in different ways. Whereas General + Stem knowledge enhanced selective retrieval and integration of the stem facts, General knowledge supported learning of the individual stem facts, but not their integration with one another. Together, the findings indicate how malleable, domain-specific experience shapes encoding, integration, and flexible extension of new, related information.