The role of growth factor signaling in various pathways has been an area of extensive investigation for many years. While growth factors are often essential for normal homeostasis, there is a fine balance between too little versus too much, which can lead to cancer. My lab has been interested in the plasminogen-like family of growth factors, hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP). Both of these are secreted as zymogen-like proteins (proHGF and proMSP), which are then cleaved to their active α,β-heterodimeric forms by a number of different serine proteases including matriptase and hepsin, both type II transmembrane serine proteases that are upregulated in cancer. It is notable that neither of the serine protease-like domains of HGF or MSP are active proteases. HGF and MSP signal by binding to their respective receptor tyrosine kinase receptors MET and RON, which have also been implicated in cancer. The research presented will focus on the roles of individual domains in these growth factors as well as molecular approaches to block or activate signaling pathways, where a variety of targeted strategies have led to agents that may have potential as new drugs.