As Bortezomib and Carfilzomib are approved to treat refractory multiple myeloma, 20 S proteasome has become a highly interested tumor therapeutic target. Because of drug resistance of Bortezomib and Carfilzomib, β-lactone natural products are used to treat cancer, arthritis, asthma, and Alzheimer’s diseases. Now the second generation drug candidates are developed, eg. Salinosporamide A(1). This review is aiming to encapsulate the synthetic methods of β-lactone proteasome inhibitors, lactacystin(3) and its analogs.