The Hippo signaling pathway, first identified in Drosophila, has emerged as a critical regulator for controlling the size of organs. Activation of the Hippo signaling pathway negatively regulates the Yorkie ortholog YAP in multiple organs, important in the regulation of cell proliferation, differentiation, and apoptosis during development. The Serine/Threonine protein kinases MST1 and MST2, mammalian homologs of the Drosophila Hippo kinase, play central roles in the Hippo signaling pathway in mammals. Recent studies reveal that non-canonical Hippo signaling pathways are also involved in the regulation of various other biological processes, particularly the important roles of MST1 and MST2 kinases in immune cell activation, adhesion, migration, growth, and apoptosis. In this review, we summarize the recent advances in understanding the roles of MST1 and MST2 kinases in the regulation of the functions of T lymphocytes and innate immune cells.