In this study, the strong lithological heterogeneity of the northern Sierra Nevada (California, USA) is exploited to elucidate the role of lithology on river profiles and patterns at the mountain-range scale. The analyses indicate that plutonic, metavolcanic, and quartzite bedrock generally host the steepest river reaches, whereas gentle reaches flow across non-quartzite metasedimentary rocks and fault zones. In addition, the largest immobile boulders are often in the steepest reaches, suggesting that wide joint spacing plays a role in creating steep channels, and a positive relationship between boulder size and hillslope angle highlights the coupling of the hillslope and fluvial systems. With respect to river network configurations, dendritic patterns dominate in the plutonic bedrock, with channels aligned down the slope of the range; in contrast, river reaches in the metamorphic belts are mainly longitudinal and parallel to the structural grain. River profiles and patterns in the northern Sierra Nevada, therefore, bear a strong lithological imprint related to differential erosion. These observations indicate that attempts to infer uplift and tilting of the range based on the gradients and orientations of paleochannel remnants should first account for the effect of bedrock erodibility. Indeed, the differences in gradients of Tertiary paleochannel remnants used to argue for late Cenozoic uplift of the range can be wholly explained by differences in lithology.