This review aimed to evaluate and compare the biological response (biocompatibility and cytotoxicity) of resin modified glass ionomer cement (RMGIC) in contrast to conventional glass ionomer cement (GIC) on human cells. Articles reporting parallel and split-mouth clinical trials, randomized controlled trials, non-randomized controlled trials, prospective studies, and in vitro studies on human permanent teeth that assessed the biological response of GIC and RMGIC were included. The following electronic bibliographic databases were searched using the keywords: MEDLINE/PubMed, EBSCO, Cochrane Central Register of Controlled Trials, and Google Scholar. For the risk of bias MINORS tool and the modified scale of Animal Research: Reporting of In Vivo Experiments and Consolidated Standards of Reporting Trials were used. Initial screening identified 552 studies, of which 9 articles met the inclusion criteria and were included in the study. Different parameters such as odontoblastic changes, inflammatory response, tertiary dentin formation, presence of microorganisms, morphological changes, cell viability, number, and metabolism were used to evaluate the biological response of conventional GIC and RMGICs. Conventional GIC shows lower cytotoxicity compared to RMGIC in vital pulp therapy procedures. Further, in vivo studies and long-term clinical trials are needed to compare these observations for pulp therapy using the 2 test materials.