The greatest barrier to the long-term storage of information in a biological system is the inevitability of molecular turnover. In this review, we discuss the features required of any chemical mechanism capable of overcoming this obstacle, positing that a specific type of “mnemogenic”, or memory-forming, chemical reaction is the basis of the engram. We describe how molecules as diverse as protein kinases, prions, and transcription factors can participate in mnemogenic reactions, and outline a blueprint for memory that postulates mnemogenic reactions at the synapse and in the nucleus and considers the constraints imposed by requirements for high fidelity and the ability to forget. This sort of a priori analysis may facilitate directed experimental approaches to understanding the mechanisms of lifelong memory.