Calcium and nitric oxide (NO) are two important biological messengers. Increasing evidence indicates that Ca2+ and NO work together in mediating responses to pathogenic microorganisms and MAMPs (Microbe Associated Molecular Patterns). Ca2+ fluxes were recognized to account for NO production whereas evidence gathered from a number of studies highlights that NO is one of the key messengers mediating Ca2+ signaling. Here, we present a concise description of the current understanding of the molecular mechanisms underlying the crosstalk between Ca2+ and NO in plant cells exposed to biotic stress. Particular attention will be given to the involvement of cyclic nucleotide gated ion channels (CNGCs) and Ca2+-sensors. Notably we provide new evidence that calmodulin might be regulated at the post-translational level by NO through S-nitrosylation. Furthermore, we report original transcriptomic data showing that NO produced in response to oligogalacturonide regulates the expression of genes related to Ca2+ signaling. Deeper insight into the molecules involved in the interplay between Ca2+ and NO not only permit a better characterization of the Ca2+ signaling system but also allows us to further understand how plants respond to pathogen attack.