The mitogen-activated protein kinase (MAPK/MPK) cascade is an important intercellular signaling module that regulates plant growth, development, reproduction, and response to biotic and abiotic stresses in plants. A MAPK cascade usually consists of a MAPK kinase kinase (MAPKKK/MEKK), a MAPK kinase (MAPKK/MKK/MEK), and a MAPK. The well-characterized MAPK cascades in plant immunity to date are the MEKK1-MKK1/2-MPK4 cascade and the MAPKKK3/4/5-MKK4/5-MPK3/6 cascade. Recently, major breakthroughs have been made in understanding the molecular mechanisms associated with the regulation of immune signaling by both MAPK cascades. In this review, we highlight the most recent advances in the role of both MAPK cascades in activating plant defense and in suppressing or fine-tuning immune signaling. We also discuss the molecular mechanisms by which plants stabilize and maintain the activation of MAPK cascades during immune signaling. Based on this review, we reveal the complexity and importance of the MEKK1-MKK1/2-MPK4 cascade and the MAPKKK3/4/5-MKK4/5-MPK3/6 cascade in plant immunity, which are tightly controlled by their interacting partners or substrates.