Serous effusions constitute a significant part of the material processed and diagnosed by cytopathology laboratories. Effusions may occur in a variety of clinical settings and the differential diagnosis between these conditions often requires ancillary tests. Immunohistochemistry is still the most frequently used method in this context. However, a wide array of other methods measuring the expression of DNA, mRNA, noncoding RNA, proteins, and other compounds may be applied to the diagnosis of serous effusions, particularly in the setting of cancer, as well as to studies focusing on tumor biology and understanding of tumor progression. In addition, as serous effusions provide ideal material for molecular testing, they have in recent years assumed central role as specimens informative of prediction in the context of targeted therapy, as well as prognostication. This review discusses recent studies in this field.