The development of therapies for SARS-CoV-2 infection, based on virus biology and pathology, and of large- and small-scale randomized controlled trials, have brought forward several antiviral and immunomodulatory drugs targeting the disease severity. Casirivimab/Imdevimab monoclonal antibodies and convalescent plasma to prevent virus entry, Remdesivir, Molnupiravir, and Paxlovid nucleotide analogs to prevent viral replication, a variety of repurposed JAK-STAT signaling pathway inhibitors, corticosteroids, and recombinant agonists/antagonists of cytokine and interferons have been found to provide clinical benefits in terms of mortality and hospitalization. However, current treatment options face multiple clinical needs, and therefore, in this review, we provide an update on the challenges of the existing therapeutics and highlight drug development strategies for COVID-19 therapy, based on ongoing clinical trials, meta-analyses, and clinical case reports.