Cell fusion is ubiquitous among eukaryotes. However, little is known about the molecular mechanism. In yeast, as cells polarize growth toward the mating partner, the tip of the shmoo comes into contact with its partner, forming a zone of cell fusion. As such, the shmoo tip comprises a hub for proteins necessary for cell fusion. Fus2p, a key regulator of cell wall removal during fusion, forms a heterodimer with Rvs161p, an amphiphysin, and the complex localizes to the shmoo tip. We have shown that Rvs161p facilitates the membrane interaction required for cortical localization. However, domain mapping of Fus2p revealed that the last eight amino acids form a novel signal also required for localization, independent of Rvs161p. Point mutations and truncations in this region cause severe mating defects. Analysis of successive C-terminal Fus2p truncations suggested a model in which an auto-inhibitory mechanism interferes with localization via an upstream region. Previous evidence showed that Fus2p is retained at the shmoo tip by both Fus1p and actin-dependent pathways. Fus1p is a pheromone-induced transmembrane protein broadly localized to the shmoo tip. We find that the actin-dependent pathway requires the C-terminus, whereas the Fus1p pathway depends on more internal sequences. Thus, the C-terminal mutations affect both pathways through auto-inhibition. To identify additional proteins interacting with Fus2p, we performed a high copy suppressor screen of the C-terminal mutations, and identified Kel1p. KEL1, encoding a kelch-domain protein, was previously implicated in cell fusion, but its function in fusion is unknown. Localization suppression by Kel1p is dependent upon Fus1p, showing that it does not bypass the normal pathway. Kel1p and its homologue, Kel2p, are required for normal levels of Fus2p localization, and act through the actin-dependent pathway. Kel1p also plays a role in mating independent of Fus2p localization; a kel1 deletion reduces cell fusion despite proper Fus2p localization. Moreover, overexpression of Kel1p can weakly suppress the fusion defect of fus2∆, arguing that Kel1p has a Fus2p-independent function. Fus2p interacts with Cdc42p, a Rho-like GTPase that plays numerous roles in growth and morphogenesis, and the interaction is required for fusion. Overexpression of Kel1p suppresses the mating defect of a Cdc42p mutant that cannot bind to Fus2p, but suppression is dependent upon Fus2p. We hypothesize that Fus2p, Cdc42p and Kel1p form a complex during fusion. In support, Kel1p interacts with two different domains of Fus2p, dependent on Cdc42p. We propose that Fus2p localization is dependent on actin, Kel1p and Fus1p and that Kel1p enhances the activity of Fus2p/Cdc42p in cell fusion.