This review paper summarizes some of the most challenging issues regarding the development of electronic microsystems for the isolation, manipulation, and characterization of rare cells. Two relevant areas, namely, immunology for cancer therapy and monitoring of microbial contaminants in water, are presented as example applications which require handling of rare cells. Starting from these applications, the state of the art in electronic microsystem research is presented, and various solutions are discussed, highlighting the advantages and disadvantages of each technology and suggesting the need to integrate multiple solutions to meet the application requirements.