Rho GTPases have been shown previously to play important roles in several cellular processes by regulating the organization of the actin and microtubule cytoskeletons. However, the mechanisms of Rho GTPases that integrate the cellular responses during regeneration have not been thoroughly elucidated. The planarian flatworm, which contains a large number of adult somatic stem cells (neoblasts), is a unique model to study stem cell lineage development in vivo. Here, we focus on cdc42, which is an extensively characterized member among Rho GTPases. We found that cdc42 is required for the maintenance of epidermal lineage. Cdc42 RNAi induced a sustained increased of cell death and led to a loss of the mature epidermal cells but without affected cell division. Our results indicate that cdc42 function as an inhibitor to block the excessive apoptotic cell death in planarian epidermal regeneration and homeostasis.