At the beginning of the COVID-19 pandemic, attempts to understand and control the disease were hindered by a lack of knowledge on coronaviruses. In response to the urgent need, our lab and others utilized pooled CRISPR knockout screens to identify new facets of SARS-CoV-2 biology. The screens operate on a pool of heterogeneous cells, each mutated in a different gene by CRISPR, and use a blunt phenotypic readout of survival from virus-induced cell death. Though the method is useful to find host factors required for replication, i.e. proviral genes, it has limitations. For example, pooled screens are biased against factors that restrict infection, such as antiviral genes. There is still an urgent need to understand SARS-CoV-2 infection and innate immune responses in the human cell. To address this, we are currently developing a whole-genome semi-arrayed CRISPR screen, where each well will have a single gene knocked out. During this seminar, I will discuss optimization for genome-scale experiments and insights gained from arrayed screens on candidate genes.