Abstract: Natural products are a vital resource of innovative drugs. Traditionally, the discovery of natural compounds with novel structures faces challenges such as low efficiency, lack of direction, and difficulties in scale-up production, which hinders the development of innovative drugs derived from natural sources. Biogenetic building blocks are essential structural units for constructing natural products, and their formation, combination, and subsequent modification determine the structural characteristics of these products. Based on the biogenetic building blocks, our team developed the biogenetic building blocks-based molecular networking method and pioneered a biomimetic synthesis strategy. These innovative approaches have been successfully applied to the targeted discovery and biomimetic synthesis of natural products with unique structures, such as the Securinega alkaloids, monoterpene indole alkaloids, and acylphloroglucinol derivatives, etc. This has significantly enhanced the discovery and collective biomimetic synthesis of these novel compounds, characterized by high efficiency, simplicity, atom economy, and diversity-oriented outcomes. This review summarizes our research on efficient discovery and biomimetic synthesis strategies for natural products based on biogenetic building blocks, aiming to provide insights for the further development and application of these technologies.