Modern applications process massive data volumes that overwhelm the storage and retrieval capabilities of memory systems, making memory the primary performance and energy-efficiency bottleneck of computing systems. Although many microarchitectural techniques attempt to hide or tolerate long memory access latency, rapidly growing data footprints continue to outpace technology scaling, requiring more effective solutions. This dissertation shows that modern processors observe large amounts of application and system data during execution, yet many microarchitectural mechanisms make decisions largely independent of this information. Through four case studies, we demonstrate that such data-agnostic design leads to substantial missed opportunities for improving performance and energy efficiency. To address this limitation, this dissertation advocates shifting microarchitecture design from data-agnostic to data-informed. We propose mechanisms that (1) learn policies from observed execution behavior (data-driven design) and (2) exploit semantic characteristics of application data (data-aware design). We apply lightweight machine learning techniques and previously underexplored data characteristics across four processor components: a reinforcement learning-based hardware data prefetcher that learns memory access patterns online; a perceptron predictor that identifies memory requests likely to access off-chip memory; a reinforcement learning mechanism that coordinates data prefetching and off-chip prediction; and a mechanism that exploits repeatability in memory addresses and loaded values to eliminate predictable load instructions. Our extensive evaluation shows that the proposed techniques significantly improve performance and energy efficiency compared to prior state-of-the-art approaches.