Magmas erupted over the last 20 m.y. within the Central Volcanic Zone (CVZ) of the Andes are strongly differentiated and depleted in 143 Nd and enriched in 87 Sr and 18 O ( 87 Sr/ 86 Sr >0.705, 143 Nd/ 144 Nd <0.5126, δ 18 O >+6.5‰) relative to intra-oceanic arc magmas. These characteristics may reflect closed-system differentiation from melts of an incompatible element enriched sub-arc mantle (ancient subcontinental lithosphere), or the ubiquitous crustal contamination of island arc-like primitive magmas, derived from an asthenospheric mantle source. It is not possible to choose unambiguously which of these models is applicable, since all of the observed lavas of the CVZ are differentiated relative to melts that could have been in equilibrium with the mantle. We contend that the evidence currently available favors the latter possibility. CVZ volcanic centers are located on exceptionally thick (c. 70 km) continental crust and parent magmas are likely to have ponded and differentiated extensively at one or more levels in the crust during ascent. Furthermore, some compositional characteristics (e.g., δ 18 O >+6.5‰—greater than the δ 18 O values expected from ultramafic mantle; and Pb isotope ratios that exhibit a correspondence with the Pb-isotope composition of the crust through which the magmas were erupted) are consistent with crustal contamination of mantle-derived magmas, rather than closed-system differentiation of mantle-derived magmas, as the process predominantly determining magma evolution in the central Andes.