Protein kinases are evolutionarily crafted into two functional states. In response to stimuli, kinase, which is usually populated in an inactive state, becomes active. Here, we outline a unified scheme to explain how kinases are activated physiologically and pathologically, focusing on RAF allosteric activation. Key concepts include the population shift from the inactive to the active state is relative; the relative populations are altered additively via allosteric events; and the structural features of the active conformation are coupled with the regulatory and catalytic spines to align the catalytic sequence motifs. This structural insight clarifies why the prerequisite of RAF dimerization, how the V600E oncogenic mutation activates RAF, how a RAF inhibitor executes paradoxical activation, and provides pharmaceutical guidelines.