Entry of β-elemene into various phases of clinical trials advocates its significance as a premium candidate likely to gain access to mainstream medicine. Based on the insights gleaned from decades of research, it seems increasingly transparent that β-elemene has shown significant ability to modulate multiple cell signaling pathways in different cancers. We partition this multicomponent review into how β-elemene strategically modulates various signal transduction cascades. We have individually summarized regulation of tumor necrosis factor related apoptosis-inducing ligand, signal transducers and activators of transcription, transforming growth factor/SMAD, NOTCH, and mammalian target of rapamycin pathways by β-elemene. Last, we will discuss the results of clinical trials of β-elemene and how effectively we can use these findings to stratify patients who can benefit most from β-elemene. © 2019 Wiley Periodicals, Inc.