Alkalinization of the external environment represents a stress situation for Saccharomyces cerevisiae. Adaptation to this circumstance involves the activation of diverse response mechanisms, whose components are still largely unknown. We show here that mutation of members of the cell integrity Pkc1/Slt2 MAP kinase module, as well as upstream and downstream elements of the system confers sensitivity to alkali. Alkalinization results in a fast and transient activation of the Slt2 MAP kinase that depends on the integrity of the kinase module and is largely abolished by sorbitol. Lack of Wsc1, removal of specific extracellular and intracellular domains or substitution of Y303 in this putative membrane stress sensor, renders cells sensitive to alkali and considerably decreases alkali-induced Slt2 activation. In contrast, constitutive activation of Slt2 by the bck1-20 allele increases pH tolerance in a wsc1 mutant. DNA microarray analysis revealed that several genes encoding cell wall proteins, such as GSC2/FKS2, DFG5, SKT5 and CRH1 are, at least in part, induced by high pH in a Slt2-dependent manner. We observe that dfg5, skt5, and particularly dfg5 skt5 cells, are alkali sensitive. Therefore, our results show that an alkaline environment imposes a stress condition on the yeast cell wall. We propose that the Slt2-mediated MAPK pathway plays an important role in the adaptive response to this insult, and that Wsc1 participates as an essential cell surface pH sensor. Moreover, these results provide a new example of the complexity of the response in budding yeast to the alkalinization of the environment.