This review presents a broad aspect of smart material‐integrated systems for isolating and profiling rare circulating tumor cells (CTCs) and circulating tumor microemboli (CTM) to provide physiological, biological, and mechanistic insights into cancer research. In particular, CTCs/CTM have emanated as essential pieces of evidence that can reveal clonal evolution, tumor heterogeneity, and disease progression within the metastatic cascade. Morphologies, cellular compositions, and rarity of CTCs/CTM make them difficult to track and isolate for profiling distinct molecular characteristics in the case of metastatic potential. Accordingly, with the advanced‐characterization techniques, examining the aspects of the specific surface markers of CTCs/CTM, epithelial‐to‐mesenchymal (EMT), mesenchymal‐to‐epithelial (MET) transitions, and timing of tumor cell dissemination would assist us to understand cancer biology and metastatic characteristics. Existing clinical and research methods for the enrichment and isolation of these sporadic cells depend on mainly conventional methods with low‐yield and expensive features. Owing to their specialized functions and analytical performances, smart material‐based technologies hold an enormous impact not only on cell detection, but also on cell isolation for downstream analyses. Herein, the main reasons for cell isolation are discussed and the recent developments in CTCs/CTM approaches for identifying further methods and future perspectives are elaborated on.