The participation of extranuclear steroid receptor signaling in organ physiology and the impact for pathobiology has increasingly been demonstrated. Important functions of membrane estrogen receptors in the cardiovascular system demonstrate new mechanisms of rapid steroid signaling to gene regulation, preventing cardiovascular disease and maintaining healthy arterial function. In cancer cells, kinase signaling initiated by extranuclear estrogen, progesterone, and androgen receptors modulates transcriptional events in the nucleus, which in turn regulate proliferation, migration, and invasion. Important mediators of cross talk between cytoplasmic and nuclear steroid receptor signaling are the proline-, glutamic acid-, and leucine-rich protein-1 and paxillin proteins, both of which modulate membrane and nuclear receptor pool signaling to promote a variety of cell biological functions.