THE STEROID and thyroid hormones circulate in the plasma tightly bound by albumin and by specific plasma globulins (1, 2). Consequently, hormones exist in two states at equilibrium in vitro, i.e. free (dialyzable) and protein-bound. A widely held hypothesis in endocrinology is that the fraction of hormone that is free in vitro is equivalent to the fraction of hormone that is free and available for transport into tissues in vivo. Therefore, in vitro measurements of free hormones may be commonly used as reliable indices of the free hormone in vivo for a variety of clinical states. The purpose of this review is to advance the concept that the large protein-bound moiety of plasma hormone is available for transport into tissues. Consequently, the fraction of plasma hormone that is available for transport in vivo may deviate greatly from the free fraction in vitro. Under some conditions, changes in the free hormone fraction in vitro and in the fraction of plasma hormone that is available for transport in vivo will be proportional.