Chronic obstructive pulmonary disease (COPD) is a major increasing health problem and the World Health Organization (WHO) reports COPD as the fifth leading cause of death worldwide. COPD refers to a condition of inflammation and progressive weakening of the structure of the lung as well as irreversible narrowing of the airways. Current treatment is only palliative and no available drug halts the progression of the disease. Human neutrophil elastase (HNE) is a serine protease, which plays a major role in the COPD inflammatory process. The protease/anti‐protease imbalance leads to an excess of extracellular HNE hydrolyzing elastin, the structural protein that confers elasticity to the lung tissue. Although HNE was identified as a therapeutic target for COPD more than 30 years ago, only Sivelestat (ONO‐5046), an HNE inhibitor from Ono Pharmaceutical, has been approved for clinical use. Nevertheless, Sivelestat is only approved in Japan and its development in the USA was terminated in 2003. Other inhibitors in pre‐clinical or phase I trials were discontinued for various reasons. Hence, there is an urgent need for low‐molecular‐weight synthetic elastase inhibitors and the present review discusses the recent advances on this field covering acylating agents, transition‐state inhibitors, mechanism‐based inhibitors, relevant natural products, and major patent disclosures.