Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through protein kinase C (PKC)-β and the phosphatidylinositol 3-kinase/AKT pathway to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. In contrast to previous PKC inhibitors, enzastaurin is very well tolerated with a favorable safety profile, allowing it to be dosed for extended durations. In the present review, we summarize the rationale for targeting PKC in cancer, the preclinical experience of enzastaurin, and the clinical findings of the current phase I and II studies. Based on the combined information, we present the rationale for its future assessment in the treatment of lung cancer.