[Abstract] Background The exact mechanism of learning and memory is still unclear, existing researchs focused on learning and memory regulatory factors, especially on positive regulatory factors. In recent years, the roles of learning and memory negative regulatory factors in correct forming and maintaining of the learning and memory has attracted most attention.Objective Summary of the role of learning and memory negative regulatory factors in the formation and maintain mechanism of learning and memory. Contents The negative regulatory factors of learning and memory mainly includes protein phosphatase, cyclic nucleotide phosphodiesterases, transcriptional regulation factor, histone deacetylases,HGN gene and so on. They regulating learning and memory in multiple levels including the cell membrane receptors, cytoplasmic signal transduction cascade composition, transcriptional regulation of gene expression in the nucleus and cell growth and development. Trend In-depth study of learning and memory negative regulatory factors and the balance between learning and memory positive/negative regulation contribute to people's understanding of the formation and maintain mechanism of learning and memory and search for effective interventions.