CB(1) receptor cellular signal transduction is dependent on the expression of G proteins to which the receptor couples, the potential for precoupling of particular G proteins to the receptors either by scaffolding mechanisms or colocalization in lipid raft domains, and the effector mechanisms that these transducer molecules regulate. This discourse will evaluate studies of efficacy for CB(1) receptor-Gi/o activation at the molecular level. Evidence for brain regional differences in CB(1) receptor signal transduction efficacy and agonist selectivity for G proteins will be summarized. The possibility that CB(1) receptors interact with Gs or Gq will be evaluated, and questions with regard to the constitutive activity and G protein sequestration will be posed.