Host immunity is required to clear SARS-CoV-2, and inability to clear the virus because of host or pathogen factors renders those infected at risk of poor outcomes. Estimates of those who are able to clear the virus with a- or pauci-symptomatic COVID-19 remain unclear, and dependent on widespread testing. However, evidence is emerging that in severe cases pathological mechanisms of hyper-inflammation and coagulopathy ensue, the former supported by results from the RECOVERY trial demonstrating a reduction in mortality with dexamethasone in advanced COVID-19. It remains unclear whether these pathogenic pathways are secondary to a failure to clear the virus because of maladaptive immune responses or if these are sequential COVID-19 defining illnesses. Understanding the pathophysiological mechanisms underpinning these cascades is essential to formulating rationale therapeutic approaches beyond the use of dexamethasone. Here we review the pathophysiology thought to underlie COVID-19 with clinical correlates and the current therapeutic approaches being investigated.