We present a first-principle computational modeling investigation, based on density functional theory (DFT) and time-dependent DFT, on the structural, electronic, optical, and charge generation properties of the semiconductor/dye/catalyst heterointerfaces in a prototypical dye-sensitized photoanode for water oxidation. The investigated architecture comprises a Ru(II) dye-sensitized TiO2 substrate tethered to an IrO2 nanoparticle catalyst. Our realistic modeling strategy and quantitative analysis of the relevant interfacial hole/electron transfer reactions indicates the slow hole injection into IrO2 and the fast dye excited-state quenching to IrO2 as the primary sources of the relatively poor cell efficiency experimentally observed. On the basis of this atomistic and electronic structure information, we propose and computationally test, against a prototype dye, a new class of Ru(II) sensitizers, which show potentially improved photoelectrochemical performances. This study constitutes a first step toward the computer-assisted design of new and more efficient materials for solar fuels production through dye-sensitized photoelectrochemical cells.