About 6% of the global population has been infected with SARS-CoV-2 to date, with more than 6 million death cases and tens of thousands still undergoing treatment. Although government restrictions are being gradually lifted in many countries, the lingering possibility of severe future infection waves requires an ongoing understanding of key SARS-CoV-2 pathological attributes. Our group has conducted the largest survey of SARS-CoV-2 host protein interaction maps to date, which aims to reveal key host- and variant-specific protein interactions. This groundwork led to the seminal collection of large-scale datasets that address important questions pertaining to key common and variant-specific SARS-CoV-2 pathological mechanisms for fine-tuning the development of more effective SARS-CoV-2 therapeutics.