Vernolide-A and vernodaline are sesquiterpene lactones isolated from genera of Vernonia. Vernolide-A and vernodaline have shown promising therapeutic properties, including antibacterial, antihelminth, and antioxidant activities. Recently, the anticancer properties of these sesquiterpene lactones have been investigated with the elucidation of effects on cell proliferation, metastasis, angiogenesis, and apoptosis. The antiproliferation and antimetastatic activities arise from targeting extracellular signal-regulated kinase 1 (ERK-1), extracellular signal-regulated kinase 2 (ERK-2), nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (STAT3), matrix metalloproteinase 2 (MMP-2), and matrix metalloproteinase 9 (MMP9). The induction of apoptosis is due to the enhancement of caspase 9, caspase 3, while inhibition of Bcl-2 and Bcl-xL results in the release of cytochrome c into the cytosol. The activity of vernolide-A and vernodaline is hypothesized to be due to thiol reactivity through the α-methylene-γ-lactone group of sesquiterpene lactones. This review will give a brief summary of the anticancer activity of vernolide-A and vernodaline and provide information on the underlying molecular mechanisms.