Proteases play important roles in plant innate immunity. In this mini-review, we describe the current view on the role of a plant protease, vacuolar processing enzyme (VPE), and the first identified plant caspase-1-like protein, in plant immunity. In the past several years, VPEs were determined to play important roles in various types of cell death in plants. Early studies demonstrated the identification of VPE as a vacuolar hydrolytic protein responsible for maturation of vacuolar proteins. Later, Nicotiana benthamiana VPE was reported to mediate virus-induced hypersensitive response by regulating membrane collapse. The ortholog of VPE in Arabidopsis is also suggested to be involved in both mycotoxin-induced cell death and developmental cell death. However, the role of VPE in elicitor-signaling is still unclear. Our recent studies demonstrated the involvement of VPE in elicitor signal transduction to induce stomatal closure and defense responses, including defense gene expression and hypersensitive cell death.