The imbalance between human neutrophil elastase (HNE) and endogenous serine proteinase inhibitors is considered to cause a variety of HNE-mediated inflammatory disorders. Thus, HNE has been the object of intensive research to find potent inhibitors that target its destructive and pro-inflammatory action. This review focuses on natural compounds which have been demonstrated to inhibit the enzyme itself or its release from neutrophils. Some of the natural compounds discussed here may serve as lead structures suitable to be used for the development of semi-synthetic inhibitors, but up to now none has been found active enough to be directly used in therapy.