In this review, we highlight potential points of therapeutic intervention in ubiquitin/ISG15 pathways involved in key host–pathogen interactions, such as PLpro, USP18, TRIM25, CYLD, A20, and others that could be targeted for the treatment of COVID-19, and which may prove effective in combatting current and future vaccine-resistant variants of the disease. Here, CYLD is linked to COVID-19.