The perinucleolar compartment (PNC) is a dynamic nuclear body found in the periphery of the nucleolus of malignant solid tumor cells. PNC contains a mixture of RNA polymerases and RNA-binding proteins. PNC is found only in cancer and not in normal cells. Its prevalence in cancer cells, whether in transformed cell lines or cancer patients’ samples, can be quite variable and is highly prevalent in metastatic tumors and metastatically transformed cell lines where it may reach 100%. Comparison of PNC prevalence in human cancer and normal tissue shows that PNC is much more prevalent in different types of solid malignancies. PNC can be detected in cancer tissues by immunolabeling techniques with antibodies against polypyrimidine tract-binding protein, an integral component of PNC. A high PNC prevalence is associated with worse clinical parameters in ovarian, colorectal, and breast cancers. In this aspect PNC functions as an important prognostic marker that indicates when more aggressive therapy is needed. Metarrestin is a newly characterized small molecule that can disassemble the PNC without excessive toxicity to normal cells, thus presenting a novel strategy in cancer treatment. Recent studies and current trials have emphasized the role of PNC as a targetable structure with significant therapeutic implications.