Today’s largest data processing workloads are hosted in cloud data centers. Due to unprecedented data growth and the end of Moore’s Law, these workloads have ballooned to the hyperscale level, encompassing billions to trillions of data items and hundreds to thousands of machines per query. Enabling and expanding with these workloads are highly scalable data center networks that connect up to hundreds of thousands of networked servers. These massive scales fundamentally challenge the designs of both data processing systems and data center networks, and the classic layered designs are no longer sustainable. Rather than optimize these massive layers in silos, we build systems across them with principled network-centric designs. In current networks, we redesign data processing systems with network-awareness to minimize the cost of moving data in the network. In future networks, we propose new interfaces and services that the cloud infrastructure offers to applications and codesign data processing systems to achieve optimal query processing performance. To transform the network to future designs, we facilitate network innovation at scale. This dissertation presents a line of systems work that covers all three directions. It first discusses GraphRex, a network-aware system that combines classic database and systems techniques to push the performance of massive graph queries in current data centers. It then introduces data processing in disaggregated data centers, a promising new cloud proposal. It details TELEPORT, a compute pushdown feature that eliminates data processing performance bottlenecks in disaggregated data centers, and Redy, which provides high-performance caches using remote disaggregated memory. Finally, it presents MimicNet, a fine-grained simulation framework that evaluates network proposals at datacenter scale with machine learning approximation. These systems demonstrate that our ideas in network-centric designs achieve orders of magnitude higher efficiency compared to the state of the art at hyperscale.