Evidence for chemical and lithological heterogeneity in the Earth’s convecting mantle is widely acknowledged, yet the major element signature imparted on mantle melts by this heterogeneity is still poorly resolved. In this study, a recent thermodynamic melting model is tested on a range of compositions that correspond to potential mantle lithologies (harzburgitic to pyroxenitic), to demonstrate its applicability over this compositional range, in particular for pyroxenite melting. Our results show that, despite the model’s calibration in peridotitic systems, it effectively reproduces experimental partial melt compositions for both Si-deficient and Si-excess pyroxenites. Importantly, the model accurately predicts the presence of a free silica phase at high pressures in Si-excess pyroxenites, indicating the activation of the pyroxene–garnet thermal divide. This thermal divide has a dominant control on solidus temperature, melt productivity and partial melt composition. The model is used to make new inferences on the link between mantle composition and melting behaviour. In silica-deficient and low-pressure (olivine-bearing) lithologies, melt composition is not very sensitive to source composition. Linearly varying the source composition between peridotite and basaltic pyroxenite, we find that the concentration of oxides in the melt tends to be buffered by the increased stability of more fusible phases, causing partial melts of even highly fertile lithologies to be similar to those of peridotite. An exception to this behaviour is FeO, which is elevated in partial melts of silica-deficient pyroxenite even if the bulk composition does not have a high FeO content relative to peridotite. Melt Al$2$O$3$ and MgO vary predominantly as a function of melting depth rather than bulk composition. We have applied the thermodynamic model to test the hypothesis that Fe-rich mantle melts such as ferropicrites are derived by partial melting of Si-deficient pyroxenite at elevated mantle potential temperatures. We show that the conspicuously high FeO in ferropicrites at a given MgO content does not require a high-Fe mantle source and is indeed best matched by model results involving around 0–20% melting of silica-deficient pyroxenite. A pyroxenite source lithology also accounts for the low CaO content of ferropicrites, whereas their characteristic low Al$2$O$3$ is a function of their high pressure of formation. Phanerozoic ferropicrites are exclusively located in continental flood basalt (CFB) provinces and this model of formation confirms that lithological heterogeneity (perhaps recycled oceanic crust) is present in CFB mantle sources.