Complex immune response to infection has been highlighted, more than ever, during the COVID-19 pandemic. This review explores the immunomodulatory treatment of moderate-to-severe forms of this viral sepsis in the context of specific immunopathogenesis. Our objective is to analyze in detail the existing strategies for the use of immunomodulators in COVID-19. Immunomodulating therapy is very challenging; there are still underpowered or, in other ways, insufficient studies with inconclusive or conflicting results regarding a rationale for adding a second immunomodulatory drug to dexamethasone. Bearing in mind that a "cytokine storm" is not present in the majority of COVID-19 patients, it is to be expected that the path to the adequate choice of a second immunomodulatory drug is paved with uncertainty. Anakinra, a recombinant human IL-1 receptor antagonist, is a good choice in this setting. Yet, the latest update of the COVID-19 Treatment Guidelines Panel (31 May 2022) claims that there is insufficient evidence to recommend either for or against the use of anakinra for the treatment of COVID-19. EMA's human medicines committee recommended extending the indication of anakinra to include treatment of COVID-19 in adult patients only recently (17 December 2021). It is obvious that this is still a work in progress, with few ongoing clinical trials. With over 6 million deaths from COVID-19, this is the right time to speed up this process. Our conclusion is that, during the course of COVID-19, the immune response is changing from the early phase to the late phase in individual patients, so immunomodulating therapy should be guided by individual responses at different time points.