Quantum software can be a force multiplier that can significantly shorten the timeline for utility-scale results from quantum hardware. In particular, several key research directions will help realize practical quantum advantage. Physics-aware, cross-layer optimizations will continue to yield important efficiencies to allow applications to make the most of quantum resources. Software-directed noise-aware optimization and error correction, in particular, will be key to increasing gate depths and maintaining acceptable output fidelity. Pulse-level optimizations and specialized native gates will also be key enablers. Additionally, applications will be hybrid computations involving high-performance classical resources as well as quantum hardware serving as special-purpose accelerators. Effectively partitioning computations between these classical and quantum resources will be necessary to support realistic applications. Additionally, deep compiler optimization and classical simulation of Clifford and near-Clifford circuits can also be important classical investments towards more efficient quantum computations.