Although phospholipase C-gamma (PLC-gamma) participates in cellular mitogenesis, evidence indicates that the catalytic activity of PLC-gamma (to hydrolyze certain phosphoinositides) is nonessential to the process. So how is it that PLC-gamma is necessary but its lipase activity is not? Recently published results from Snyder and colleagues describe the ability of PLC-gamma to facilitate guanine nucleotide exchange for the recently identified nucleus-localized GTPase PIKE, which acts to enhance the enzymatic activity of phosphatidylinositol 3'-kinase (PI3K). The authors contend that the SH3 domain, rather than the catalytic domain, of PLC-gamma is required for aiding PIKE, and furthermore, that the mitogenic activity of PLC-gamma depends not on its phospholipase activity, but rather on its interaction with PIKE. Wang and Moran examine the results and piece together a picture of how PLC-gamma cooperates with PIKE.