Angiotensin-converting enzyme 2 (ACE2), a second angiotensin-converting enzyme (ACE), regulates the renin-angiotensin system by counterbalancing ACE activity. Accumulating evidence in recent years has demonstrated a physiological and pathological role of ACE2 in the cardiovascular systems. Recently, it has been shown that severe acute respiratory syndrome (SARS) coronavirus, the cause of SARS, utilizes ACE2 as an essential receptor for cell fusion and in vivo infections in mice. Intriguingly, ACE2 acts as a protective factor in various experimental models of acute lung failure and, therefore, acts not only as a key determinant for SARS virus entry into cells but also contributes to SARS pathogenesis. Here we review the role of ACE2 in disease pathogenesis, including lung diseases and cardiovascular diseases.