In this review, we discuss the poorly explored role of calcium/calmodulin‐dependent protein kinase II (Ca MKII) in memory maintenance, and its influence on memory destabilization. After a brief review on Ca MKII and memory destabilization, we present critical pieces of evidence suggesting that Ca MKII activity increases retrieval‐induced memory destabilization. We then proceed to propose two potential molecular pathways to explain the association between Ca MKII activation and increased memory destabilization. This review will pinpoint gaps in our knowledge and discuss some ‘controversial’ observations, establishing the basis for new experiments on the role of Ca MKII in memory reconsolidation. The role of Ca MKII in memory destabilization is of great clinical relevance. Still, because of the lack of scientific literature on the subject, more basic science research is necessary to pursue this pathway as a clinical tool.