Genetic evidence supporting a therapeutic target substantially improves the probability of successful drug development, as genetic variation can be used to draw causal inferences. Findings reveal that critical illness in Covid-19 is related to at least two biological mechanisms: innate antiviral defences, which are important early in the disease (e.g., IFNAR2 and OAS genes), and host-driven inflammatory lung injury, a key mechanism of late, life-threatening Covid-19 (e.g., DPP9, TYK2, and CCR2). Mendelian randomisation results implying a causal role for IFNAR2 and TYK2 are statistically significant in confirmatory analyses, and the association with critical illness for genotype-inferred CCR2 expression is particularly strong in lung tissue. Additionally, the ABO locus was previously associated with Covid-19 but was not genome-wide significant in the GenOMICC critically ill cohort. Interestingly, patients admitted to intensive care units in the UK during the first wave of Covid-19 were, on average, younger and less burdened by comorbid illness than the broader hospitalised population. Further studies are urgently needed to deepen these findings.