Over the last two years, 10 new high-resolution structures of G protein-coupled receptors (GPCRs), either with antagonist bound or in an active-like state, have been solved. Whilst the structures of bovine opsin and squid rhodopsin were determined using protein purified from native sources, a rhodopsin mutant structure, the structures of the beta(1) and beta(2) adrenergic receptors and the adenosine A(2a) receptor were determined from engineered protein heterologously expressed in either insect or mammalian cells. These results are the culmination of years of careful work and have resulted in three new strategies for structure determination of GPCRs that can be applied to virtually any membrane protein. Structural and functional investigations have defined a number of conserved interaction networks between key residues in GPCRs that are probably important for receptor structure and activation. Recent evidence indicates that these networks could be disrupted and rearranged independently from each other, suggesting a possible mechanism for full and partial receptor activation. In addition, one of the opsin structures suggests how one of the highest conserved residues in GPCRs, Arg135(3.50) of the (E/D)RY motif in TM3, interacts directly with a bound peptide derived from the carboxy terminus of the alpha-subunit of the G protein (G(alpha)t). This result sets the basis for the elucidation of the relationship between the conformational changes in the receptor and activation of the G protein.