Owing to high strain energy, molecules with trans-fused bicyclo[3.3.0]octane ring systems are very difficult to synthesize, and there are very few approaches to access them. Recently, a number of natural products with such ring systems have been made by the synthetic community. However, there has been no review in this field before. This review provides a systematic and comprehensive discussion on the synthesis of natural products containing trans-fused bicyclo[3.3.0]octanes and the historical context of this work. The prospects for future research in this field are also discussed. Covering the literature before 2021, this review aims to offer a helpful reference for total synthesis of highly strained natural products containing trans-fused bicyclo[3.3.0]octane ring systems.