As COVID-19 cases continue to surge nationwide, the newly approved COVID-19 vaccines cannot come soon enough. Although higher education institutions (HEIs) are not at the top of the priority list to receive scarce early doses of the vaccine, colleges and universities should prepare for how they will handle vaccination on their campuses. In general, both public and private HEIs may mandate that their staff receive the COVID-19 vaccine once it becomes available to the general public and may discipline an employee who refuses to receive the vaccine without cause. In practice, however, HEIs should be aware that staff may be entitled to medical exemptions under the Americans with Disabilities Act (ADA) and religious exemptions under Title VII. This article offers considerations for colleges and universities mandating the COVID-19 vaccine for employees.