Proteins with VQ motif (VQs) are emerging modulators of plant immunity. This study aimed to dissect the role of the family of VQ genes encoded by the genome of Arabidopsis thaliana in responses to pathogens. In particular, targeting of two subclasses of the VQs (ten proteins in total) by two mitogen-activated protein kinases (MAPKs) could be observed in yeast two-hydrid assays and in vitro phosphorylation reactions. In addition, the VQs which were substrates for MAPKs were also able to interact with WRKY proteins – a large class of plant transcription factors. As shown by mutagenesis and domain swap experiments, the presence of a functional VQ motif proved to be essential for this interaction. Strikingly, an elicitor-triggered phosphorylation of the VQs in an Arabidopsis protoplast system led to a rapid degradation of the proteins, whereas mutant VQs with disturbed phosphorylation sites were much more stable. Over-expression of one VQ in Arabidopsis decreased the plant’s ability to build up an induced resistance. Based on studies on defense promotor activation, two hypotheses for the interplay of MAPKs, VQs, and WRKYs in plant defense signaling are presented.