The development of molecular biology methods in the early 1980s led to a better understanding of the role of transcription factors in mammalian cells. The discovery that some transcription factors are critically important for cells to switch between different functional states was fundamental for modern molecular neurobiology. In the 1980s Leszek Kaczmarek proposed that, analogically to the cell cycle or to cell differentiation, long‑term synaptic plasticity, learning, and memory should also require the activity of transcription factors. To test his hypothesis, he focused on c‑Fos. His team showed that the c‑Fos proto‑oncogene is activated by synaptic plasticity and learning, and is required for these phenomena to occur. Subsequent studies showed that timp‑1 and mmp‑9 are c‑Fos effector genes that are required for plasticity. The present review summarizes Kaczmarek's hypothesis and the major evidence that supports it. We\r\nalso describe the ways in which knowledge of the molecular neurobiology of learning and memory advanced because of Kaczmarek's theory. Finally, we briefly discuss the degree to which his hypothesis holds true today after the discovery of non‑coding RNAs, a novel class of regulatory molecules that were not taken into account by Leszek Kaczmarek in the 1980s.