The activated partial thromboplastin time (PTT) is the principal method by which laboratories monitor unfractionated heparin therapy. A review of the experimental basis for heparin monitoring by the PTT reveals significant shortcomings of the assay. The availability of anti-Xa heparin assays on automated coagulation analyzers presents a seemingly logical alternative because the PTT therapeutic range is derived from anti-Xa measurements of plasma from heparinized patients. The anti-Xa assay is not susceptible to many of the preanalytical interferences affecting the PTT, and adoption of anti-Xa monitoring would eliminate the need for validating a PTT therapeutic range. However, anti-Xa heparin monitoring has not been rigorously validated by clinical outcomes studies, and decreasing clinical use of unfractionated heparin makes it unlikely that such data is forthcoming. Nonetheless, many laboratories may find themselves in the position of being unable to continue to validate their PTT therapeutic ranges according to current recommendations and accreditation requirements.