In the era of nanoscale technology scaling, we are facing the limits of physics, challenging robust and reliable microprocessor design and fabrication. As these trends continue, guaranteeing correctness of execution is becoming prohibitively expensive and impractical. In this thesis, we demonstrate the benefits of abstracting circuit-level challenges to the architecture and software layers. Reliability challenges are broadly classified into process, voltage, and thermal variations. As proof of concept, we target voltage variation, which is least understood, demonstrating its growing detrimental effects on future processors: Shrinking feature size and diminishing supply voltage are making circuits more sensitive to supply voltage fluctuations within the microprocessor. If left unattended, these voltage fluctuations can lead to timing violations or even transistor lifetime issues. This problem, more commonly known as the dI/dt problem, is forcing microprocessor designers to increasingly sacrifice processor performance, as well as power efficiency, in order to guarantee correctness and robustness of operation. Industry addresses this problem by un-optimizing the processor for the worst case voltage flux. Setting such extreme operating voltage margins for those large and infrequent voltage swings is not a sustainable solution in the long term. Therefore, we depart from this traditional strategy and operate the processor under more typical case conditions. We demonstrate that a collaborative architecture between hardware and software enables aggressive operating voltage margins, and as a consequence improves processor performance and power efficiency. This co-designed architecture is built on the principles of tolerance, avoidance and elimination. Using a fail-safe hardware mechanism to tolerate voltage margin violations, we enable timing speculation, while a run-time hardware and software layer attempts to not only predict and avoid impending violations, but also reschedules instructions and co-schedules threads intelligently to eliminate voltage violations altogether. We believe tolerance, avoidance and elimination are generalizable constructs capable of acting as guidelines to address and successfully mitigate the other parameter-related reliability challenges as well.