The activation of growth factor receptors plays an essential role in the pathogenesis and progression of several human cancers, including pancreatic ductal adenocarcinoma (PDAC). Because PDAC, with an overall median survival of about 6 months, is resistant to most current chemotherapeutic regimens, investigation of growth factor signaling networks is a highly attractive research target for the development of new therapeutic compounds. A large number of growth factors and their receptors are upregulated by epigenetic alterations in PDAC and influence different aspects of the tumor pathophysiology. The complex epidermal growth factor system is the best characterized network that influences proliferation, migration, differentiation, and apoptosis of cancer cells. Growth factor–mediated disease progression in PDAC also involves the loss of inhibitory signaling (eg, the transforming growth factor–β system), stimulation of angiogenesis (eg, the vascular endothelial growth factor system), tumor-stromal crosstalk (eg, the hepatocyte growth factor system), and other molecular mechanisms. Although there are increasing numbers of clinical trials using monoclonal antibodies or tyrosine kinase inhibitors to block growth factor activation, these drugs have not yet entered the first-line treatment regimen for PDAC, in contrast to other cancers, such as carcinoma of the breast or colon. This review provides an updated outline of growth factor receptor activation in PDAC.