Controlled human infection models (CHIs) are studies in which healthy human volunteers are experimentally infected with SARS-CoV-2 in order to identify the effectiveness of potential drug and vaccine candidates. This analysis assessed the major risks of a CHI model as well as discussed potential mitigation strategies to address each identified risk. The primary risk of a CHI model is that a subject may develop severe disease; such a risk can be partly addressed by having rescue treatment options, selecting low-risk participants, and lowering the initial viral inoculum dose. These measures would also help decrease the risk of developing long-term sequelae, which are thought to be associated with severe disease. Nonetheless, adequate compensation mechanisms need to be implemented in the case that such events arise for the participant. Additionally, it is possible that the infected participant may trigger large-scale community transmission through infecting healthcare personnel or household contacts. Therefore, public health authorities must be alerted to trace potential transmission and subjects must adhere to a strict quarantine while they may be infectious. Lastly, isolated participants should initially undergo mental health screenings to minimize the impact of an unexpected lengthy quarantine. While risks of CHI models may be mitigated, the overall benefit of these studies should be weighed against the remaining risk.