Yeast two-hybrid (Y2H) screening of a prostate cDNA library with the cDNA for sex hormone-binding globulin (SHBG) has been used to identify proteins through which SHBG may exert autocrine or paracrine effects on sex steroid target tissues. The library screen gave 230 positive interactions of which around 60 have been sequenced. Of the proteins identified to date from database (BLAST) searches of these sequences, SHBG is one of those occurring most frequently. Amongst the proteins of interest are the membrane-associated proteins flotillin-1 and PRV-1, the enzymes cathepsin D, kallikrein 4 and acid phosphatase, various metallothioneins and translation elongation factor 1 alpha. The significance of the interaction of SHBG with these proteins is discussed.