Transitioning to zero CO2 across the electric sector and economy can pose challenges and opportunities for reliability, stemming from greater shares of variable renewable energy, energy storage, end-use electrification, electricity-derived fuels, and distributed energy resources. This study employs EPRI's in-house energy system modeling framework, the U.S. Regional Economy, Greenhouse Gas, and Energy Model (US-REGEN), to identify technology pathways in the electric sector to reach economy-wide net-zero CO2 by 2050 and a detailed commercial capacity planning and grid operations simulation model, to identify potential reliability challenges for each pathway. Results reveal that completely phasing out existing flexible dispatchable generation by 2050 presents significant reliability challenges, primarily due to the variability of renewable energy sources, coupled with lack of firm capacity options. The research also underscores the value of identifying potential deficiencies in intra-regional transmission and investing in new transmission infrastructure along with generation investments to improve system reliability for deep decarbonization.