New major and trace element and Sr, Nd, and Pb isotope data, together with 39Ar-40Ar ages for lavas from the extinct Galapagos Rise spreading center in the eastern Pacific reveal the evolution in magma compositions erupted during slowdown and after the end of active spreading at a mid-ocean ridge. Lavas erupted at 9.2 Ma, immediately prior to the end of spreading are incompatible element depleted mid-ocean ridge tholeiitic basalts, whereas progressively younger (7.5 to 5.7 Ma) postspreading lavas are increasingly alkalic, have higher concentrations of incompatible elements, higher La/Yb, K/Ti, 87Sr/86Sr, and lower 143Nd/144Nd ratios and were produced by smaller degrees of mantle melting. The large, correlated variations in trace element and isotope compositions can only be explained by melting of heterogenous mantle, in which incompatible trace element enriched lithologies preferentially contribute to smaller degree mantle melts. The effects of variable degrees of melting of heterogeneous mantle on lava compositions must be taken into account when using mid-ocean ridge basalt (MORB) to infer the conditions of melting beneath active spreading ridges. For example, the stronger “garnet signature” inferred from Sm/Nd and 143Nd/144Nd ratios for postspreading lavas from the Galapagos Rise results from a larger contribution from enriched lithologies with high La/Yb and Sm/Yb, rather than from a greater proportion of melting in the stability field of garnet peridotite. Correlations between ridge depth and Sm/Yb and fractionation-corrected Na concentrations in MORB worldwide could result from variations in mantle fertility and/or variations in the average degree of melting, rather than from large variations in mantle temperature. If more fertile mantle lithologies are preferentially melted beneath active spreading ridges, then the upper mantle may be significantly more “depleted” than is generally inferred from the compositions of MORB.