Estramustine (EM), originally conceived as an alkylating agent, has shown potential in prostate cancer treatment due to its ability to interfere with microtubule functions, crucial for cell division and cancer growth. It binds to microtubule-associated proteins in the nuclear matrix, disrupting mitosis and inducing apoptosis in cancer cells. We tried to develop radiolabeled estramustine derivatives for radiochemotherapy, i.e., cytotoxic/radiotoxic tumor targeting agents. In our own experimental studies, we showed that estramustine phosphate (EMP) and estramustine binding protein antibody (EMBP-AB) accumulate in the mouse prostate. However, the distribution of radioiodinated EMBP-AB in tumor mice was not beneficial in radionuclide treatment as compared to possible EMP applications. We also studied how EMP acts a radiation sensitizer, and mechanisms for that were mapped in xenograft studies. The therapeutic potential of estramustine derivatives against prostate cancer remained limited. The clinical use of estramustine to chemotherapy is briefly reviewed in this chapter, but nowadays the consensus is that EM does not significantly improve overall survival or reduce high-grade toxicity, although it does increase PSA response rates, suggesting a potential benefit in disease control albeit not improving life expectancy.