Calmodulin is a Ca2+ binding protein found in many eukaryotic cells. It is one of the most important intracellular mediators of Ca2+-dependant signaling in eukaryotic cells. It regulates diverse processes including mitosis, muscle contraction and nucleotide metabolism by modulating the activity of at least 30 different target enzymes in a calcium-dependant manner. Calmodulin plays an important role in the regulation of processes, such as the assembly and disassembly of microtubules by controlling protein kinase activities, by exerting an indirect influence upon a wide variety of cellular processes. It is observed that multi-drug resistant cells have a greater intracellular concentration of calcium than non-resistant cells which contributes to their increased sensitivity to calmodulin antagonism compared with that of non resistant cells. Calmodulin mediated processes can be effectively inhibited by a variety of pharmacological agents of different chemical structures, eg:The calcium channel blocker verapamil and antipsychotic drugs like the Phenothiazines. Many bioisosteres of phenothiazines like phenoxazines and acridones have been prepared and these have also shown very good calmodulin antagonism. These calmodulin antagonists have been shown to modulate multi-drug resistance (MDR) in cancer cells. This review highlights concepts of identification and optimization of new inhibitors of calmodulin in reversing MDR in cancer cells.