Abstract2,3‐Oxidosqualene cyclases (OSC) are enzymes which convert 2,3‐oxidosqualene (OS) into polycyclic triterpenoids such as lanosterol, cycloartenol, and α‐and β‐amyrin. Our interest in the study of OSC is the development of new OSC inhibitors for potential use as hypocholesterolemic, antifungal, or phytotoxic drugs. In particular, we describe the biological activity and the mechanism of a series of acyclic azasqualene derivatives mimicking the C‐2, C‐8, and C‐20 carbonium ions formed during OS cyclization. Some of these carbonium ion analogues are very promising as specific hypocholesterolemic agents. The toxicity, the biodistribution, and the pharmacokinetics of different azasqualene derivatives in mice are also presented. In order to obtain new, site‐directed irreversible inhibitors of OSC, a series of squalene derivatives containing functional groups that can link covalently to an active‐site thiol group was designed. Among these compounds, squalene maleimide was the most active toward mammalian OSC, whereas squalene Ellman behaved as an irreversible inhibitor of OSC from yeast