The multidrug resistance (MDR) P‐glycoprotein (P‐gp) is an active transporter associated with chemoresistance of tumor cells. A fundamental aspect not yet entirely clarified is the physiological role of MDR‐P‐gp in normal mammalian tissues. In this paper we report that multidrug (chemo)resistance is already present in mouse oocytes and early cleavage embryos. Expression of MDR‐specific P‐gp is detectable by antibody (C219) staining from the primary oocyte onward to the eight‐cell embryo. MDR‐mRNA is demonstrated in mature oocytes using an MJr1‐specific cDNA probe. Functional activity of P‐gp is shown by the efficacy of MDR reversers (verapamil or quinidine) in enhancement of: 1) drug accumulation (daunomycin) in all stages investigated, 2) drug cytotoxicity (daunomycin or mitomycin C‐induced developmental impairment) in two‐cell embryos cultured for 24 h, and 3) drug cytokinesis‐blocking activity (cytochalasin D; our recent findings demonstrate cytochalasins to be substrates for P‐gp and to indicate the presence of MDR by their microfilament‐disrupting action on cycling cells) in four‐ and eight‐cell embryos cultured for 24 h. Furthermore, functional involvement of P‐gp in vivo is demonstrated. Concurrent administration of verapamil increases doxorubicin‐induced developmental impairment in the zygote stage during the first cleavage cycle in pregnant females. Results provide evidence that MDR‐P‐gp has an efficient protective function in early reproduction.— Elbling, L., Berger, W., Rehberger, A., Waldhör, T., Micksche, M. P‐Glycoprotein regulates chemosensitivity in early developmental stages of the mouse. FASEB J. 7: 1499‐1506; 1993.