3-phosphoinositide dependent protein kinase-1 (PDK1 or PDPK1), and the majority of its substrates, belong to the AGC family of kinases (related to cAMP-dependent protein kinase 1, cyclic Guanosine monophosphate-dependent protein kinase, and protein kinase C), and control a plethora of cellular processes, downstream either to PI3K or other pathways, such as RAS GTPase-MAPK (mitogen-activated protein kinase). PDPK1, one of the members of an upregulated EGF-signaling network in LRCC, mediates resistance to gemcitabine, is found to be dysregulated in pancreas cancer specimens, and might be an attractive molecular target for combination therapy studies. An increasing amount of evidence hints at PDPK1 as an intriguing and underexplored target for cancer therapy. Several reports show that PDK1 expression is dysregulated in multiple cancer types. Furthermore, PDK1 is implicated in signaling pathways frequently altered in cancer, such as PI3K/Akt, Ras/MAPK, and Myc.