Chloroquine (CQ) was initially synthesized as an antimalarial agent, but later on, it also shows immunomodulatory, anticancer, and antiviral effects in clinical practice. Although CQ has been used to treat various conditions for more than half century, the underlying mechanisms of its diverse therapeutic actions remain incomplete. In this paper, we hypothesize that targeting three-dimensional genome architecture might be one of the mechanisms of CQ’s diverse therapeutic actions. Based on this hypothesis, new approaches to the treatment and prevention of cancer and coronavirus disease 2019 (COVID-19) are proposed.