Rotavirus (RV) is the leading cause of severe gastroenteritis in young children. However, because the incorporation of live-attenuated RV vaccines as part routine childhood immunization schedules, the rates of hospitalization from RV infections have decreased significantly across the globe. While RV vaccine safety and effectiveness have been well documented in the general population, there is controversy surrounding its use in preterm and immunocompromised infants. In this article, we review current research and consensus statements on the safety of the RV vaccine, the immunogenicity of the response and the potential for transmission and shedding of the virus postvaccination in both preterm infants and immunocompromised infants. RV vaccines are well tolerated in hospitalized preterm infants with no significant increase in nosocomial infections, gastrointestinal complications or feeding difficulties. In select immunocompromised infants (such as HIV-infected or HIV-exposed infants), RV vaccine administration did not increase the rate of adverse events. However, multiple case reports noted increased rates of adverse events in infants with severe combined immunodeficiency. The risk of viral shedding and transmission between vaccinated neonates and household contacts remain low and does not outweigh the benefit of vaccination.