Cell fusion is a universal process in eukaryotic organisms. We are studying the process of cell fusion using mating of the budding yeast, S. cerevisiae. To mate, haploid yeast cells detect each other by pheromone signaling, polarize their growth toward the mating partner, and then fuse to form a diploid zygote. The initial step in yeast fusion is the removal of the cell wall between the mating partners, to allow plasma membrane fusion. Because the improper timing or location of cell wall degradation would lead to cell lysis and death, the initiation of cell fusion is a highly regulated process. The signal(s) that indicate when and where cell wall degradation should occur have not been identified. Previous hypotheses proposed that cells may require a high local concentration of mating pheromone, physical contact, an as yet unidentified protein receptor, or a combination of all three. Several pieces of evidence suggest that the cell wall integrity (CWI) pathway may play a role in this signaling. A hyperactive mutation of PKC1, a central downstream component of CWI pathway, causes a cell fusion defect. Moreover, the CWI pathway is activated by pheromone-induced morphogenesis. The five transmembrane protein sensors (Wsc1-3p, Mid2p, and Mtl1p) of the CWI signaling cascade have been suggested to act as mechanosensors. We hypothesize that cell-cell contact relieves CWI signaling to allow cell wall degradation. Loss of MID2 causes “mating-induced death” after exposure to pheromone. We find that the mating-induced death is due to localized loss of cell wall and plasma membrane integrity. Mutations in several genes required for cell fusion (FUS1, FUS2, RVS161, CDC42), but not nuclear fusion (KAR5) suppress mid2, suggesting that the mating-induced death is due to unregulated cell fusion. Fus2p functions late in mating to regulate cell wall removal and loss of Fus2p causes a block in cell fusion. Deletion of WSC1 or MID2 partially suppresses the cell fusion defect of fus2Δ,fus1Δ, rvs161-10 and cdc42-138. These data suggest a role for the CWI pathway in regulating cell wall degradation during yeast mating. Interestingly, loss of WSC1 specifically leads to zygote/diploid cell death. Although fus2Δ suppresses the phenotype of mid2Δ, it does not suppress the defect of wsc1Δ. Taken together these data suggest distinct roles for WSC1 and MID2 in cell fusion and diploid cell wall integrity.