The elucidation of signal-transduction networks regulating cell function has led to targeted cancer therapeutics focusing on specific molecular drivers, with kinases being among the most intensively studied drug targets. The accumulation of structural information on human kinases and their conformations—active for type I inhibitors, inactive for type II inhibitors which are further divided into IIA and IIB based on the position of the DFG-motif or αC-helix—has expanded knowledge of kinase structural biology and facilitated the design of potent and selective inhibitors. B-Raf has been recognized as a promising drug target since the discovery of BRAF mutations in cancer, and inhibitors like vemurafenib (a type IIB inhibitor) have shown impressive clinical results in metastatic melanoma harboring the BRAFV600E mutation. However, recent studies suggest that B-Raf inhibitors can activate the RAF-MEK-ERK signaling pathway in cells containing wild type B-Raf through Raf dimerization, a process dependent on the specific conformations induced by inhibitor binding. This perspective focuses on the conformational effects of inhibitor binding to Raf kinase and the consequences on MAPK pathway activation in B-RafWT cells, which are highly relevant to the successful clinical path of vemurafenib compared to other potent and selective B-Raf inhibitors.