Tackling the complex challenge of harvesting solar energy to generate energy-dense fuels such as hydrogen requires the design of photocatalytic nanoarchitectures interfacing components that synergistically mediate a closely interlinked sequence of light-harvesting, charge separation, charge/mass transport, and catalytic processes. The design of such architectures requires careful consideration of both thermodynamic offsets and interfacial charge-transfer kinetics to ensure long-lived charge carriers that can be delivered at low overpotentials to the appropriate catalytic sites while mitigating parasitic reactions such as photocorrosion. Here we detail the theory-guided design and synthesis of nanowire/quantum dot heterostructures with interfacial electronic structure specifically tailored to promote light-induced charge separation and photocatalytic proton reduction. Topochemical synthesis yields a metastable β-Sn 0.23 V 2 O 5 compound exhibiting Sn 5s-derived midgap states ideally positioned to extract photogenerated holes from interfaced CdSe quantum dots. The existence of these midgap states near the upper edge of the valence band (VB) has been confirmed, and β-Sn 0.23 V 2 O 5 /CdSe heterostructures have been shown to exhibit a 0 eV midgap state-VB offset, which underpins ultrafast subpicosecond hole transfer. The β-Sn 0.23 V 2 O 5 /CdSe heterostructures are further shown to be viable photocatalytic architectures capable of efficacious hydrogen evolution. The results of this study underscore the criticality of precisely tailoring the electronic structure of semiconductor components to effect rapid charge separation necessary for photocatalysis.