The cytokine-independent survival kinase (CISK) in the serum and glucocorticoid-regulated kinase family plays an important role in mediating cell growth and survival. N-terminal to its catalytic kinase domain, CISK contains a phox homology (PX) domain, a phosphoinositide-binding motif that directs the membrane localization of CISK and regulates CISK activity. We have determined the crystal structures of the mouse CISK-PX domain to unravel the structural basis of membrane targeting of CISK. In addition to the specific interactions conferred by the phosphoinositide-binding pocket, the structure suggests that a hydrophobic loop region and a hydrophilic beta-turn contribute to the interactions with the membrane. Furthermore, biochemical studies reveal that CISK-PX dimerizes in the presence of the linker between the PX domain and kinase domain, suggesting a multivalent mechanism in membrane localization of CISK.