Merkel cell carcinoma (MCC) is a rare but highly aggressive tumor of the skin. Recently, we have shown that MCC cells in situ are characterized by a complete absence of mitogen-activated protein kinase (MAPK) pathway signaling, which is preserved in the MCC cell line UISO. Here we present data suggesting that silencing of the MAPK pathway is essential for the survival of MCC cells. Activation of the MAPK pathway could be achieved by inducing a regulatable form of the c-Raf-1 kinase domain in UISO cells. Consequently, MAPK signaling led to morphological changes, loss of actin stress fibers, and induction of apoptosis, which could be prevented by the MAP kinase kinase-specific inhibitor U0126. Hence, despite the fact that activation of the MAPK pathway contributes to oncogenesis in many cancers, it seems to be a negative selection factor for MCC cells. Since ERK phosphorylation was also inducible by the Raf-activating pharmacological agent ZM336372, these results provide new perspectives for potential therapeutics for this highly aggressive tumor.