Polychlorinated biphenyls (PCBs) are among the most ubiquitous pollutants in the environment, and their metabolism leads to the formation of hydroxylated PCBs (OH-PCBs) and methyl sulfone PCBs (MeSO2-PCBs). These metabolites are generally more hydrophilic than the parent compound, and therefore are more easily eliminated from the body. However, some congeners have been shown to be strongly retained in human blood, binding to transthyretin with an affinity that is, in general, greater than that of the natural ligand thyroxin itself, which could result in toxicological effects, particularly on the thyroid system. Currently available analytical methods require, in general, extensive sample preparation, which includes a series of time-consuming and low-throughput liquid-liquid and back extractions, evaporations, several cleanup steps, and in some cases, derivatization prior to analysis by gas chromatography (GC) or liquid chromatography (LC) coupled with mass spectrometry (MS). Recent developments in the use of LC coupled with tandem MS (MS/MS) have brought some improvements in terms of sample preparation for the determination of PCB metabolites in blood, although there are still possibilities for continued development. The selected literature has evidenced few studies of LC-MS/MS-based methods, a lack of analytical standards, nonassessment of lower-chlorinated OH-PCBs, and scarce attention to MeSO2-PCBs in blood. This review aims to evaluate critically the currently available analytical methods for determination of OH-PCBs and MeSO2-PCBs in blood.