Caspofungin resistance is a great concern, as the echinocandin drugs are recommended as first-line therapy for invasive candidiasis. Echinocandin resistance is conferred by mutations in FKS genes. Nevertheless, some pathways which regulate cellular stress responses could be crucial for enabling the evolution and maintenance of drug resistance. In this work, the first objective was to identify resistant mechanisms by whole genome sequencing in echinocandin-resistant C. glabrata. Then, studies of the proteomic response to caspofungin exposure and the analysis of the impact of calcineurin inhibitors on susceptibility, stress tolerance, biofilm formation, and pathogenicity in Galleria mellonella were conducted. The caspofungin resistant isolate only presented mutation in the FKS gene. Based on proteomic results, we identified 21 proteins whose abundance changed in response to caspofungin exposure. Some of these proteins are involved in wall biosynthesis, pathogenesis, and response to stress. Also, we showed that antifungal drugs in combination with CaM/Cal inhibitors could be an excellent therapeutic option, proved in an in-vitro and in-vivo model. Results, that could be potentially used to improve the outcomes of fungal diseases, especially now that antifungal resistance is increasing.