The G12 subfamily of heterotrimeric G proteins has been the subject of intense scientific interest for more than 15 years. During this period, studies have revealed more than 20 potential G12-interacting proteins and numerous signaling axes emanating from the G12 proteins, Galpha12 and Galpha13. In addition, more recent studies have begun to illuminate the various and sundry functions that the G12 subfamily plays in biology. In this review, we summarize the diverse range of proteins that have been identified as Galpha12 and/or Galpha13 interactors and describe ongoing studies designed to dissect the biological roles of specific Galpha-effector protein interactions. Further, we describe and discuss the expanding role of G12 proteins in the biology of cells, focusing on the distinct properties of this subfamily in regulating cell proliferation, cell migration, and metastatic invasion.