Candida albicans(C. albicans) is the most frequent strain associated with cross-kingdom infections in the oral cavity. Clinical evidence shows the co-existence ofStreptococcus mutans(S. mutans) andC. albicansin the carious lesions especially in children with early childhood caries (ECC) and demonstrates the close interaction between them. During the interaction, bothS. mutansandC. albicanshave evolved a complex network of regulatory mechanisms to boost cariogenic virulence and modulate tolerance upon stress changes in the external environment. The intricate relationship and unpredictable consequences pose great therapeutic challenges in clinics, which indicate the demand forde novoemergence of potential antimicrobial therapy with multi-targets or combinatorial therapies. In this article, we present an overview of the clinical significance, and cooperative network of the cross-kingdom interaction betweenS. mutansandC. albicans.Furthermore, we also summarize the current strategies for targeting cross-kingdom biofilm.