Deep neural networks (DNNs), as a main-stream algorithm for various AI tasks, achieve higher accuracy at the cost of increased computational complexity and model size, posing great challenges to hardware platforms. This dissertation first tackles the design challenges of resistive random-access-memory (RRAM) based in-memory computing (IMC) architectures. A new metric, model stability from the loss landscape, is proposed to help shed light on accuracy under variations and model compression and guide a novel variation-aware training (VAT) solution. The proposed method effectively improves post-mapping accuracy of multiple datasets. Next, a hybrid RRAM/SRAM IMC DNN inference accelerator is developed, that integrates an RRAM-based IMC macro, a reconfigurable SRAM-based multiply-accumulate (MAC) macro, and a programmable shifter. The hybrid IMC accelerator fully recovers the inference accuracy post the mapping. Furthermore, this dissertation researches on architectural optimizations for high IMC utilization, low on-chip communication cost, and low energy-delay product (EDP), including on-chip interconnect design, PE array utilization, and tile-to-router mapping and scheduling. The optimal choice of on-chip interconnect results in up to 6x improvement in energy-delay-area product for RRAM IMC architectures. Furthermore, the PE and NoC optimizations show up to 62% improvement in PE utilization, 78% reduction in area, and 78% lower energy-area product for a wide range of modern DNNs. Finally, this dissertation proposes a novel chiplet-based IMC benchmarking simulator, SIAM, and a heterogeneous chiplet IMC architecture to address the limitations of a monolithic DNN accelerator. SIAM utilizes model-based and cycle-accurate simulation to provide a scalable and flexible architecture. SIAM is calibrated against a published silicon result, SIMBA, from Nvidia. The heterogeneous architecture utilizes a custom mapping with a bank of big and little chiplets, and a hybrid network-on-package (NoP) to optimize the utilization, interconnect bandwidth, and energy efficiency. The proposed big-little chiplet-based RRAM IMC architecture significantly improves energy efficiency at lower area, compared to conventional GPUs. In summary, this dissertation comprehensively investigates novel methods that encompass device, circuits, architecture, packaging, and algorithm to design scalable high-performance and energy-efficient IMC architectures.