During the last decades multidrug resistance (MDR) emerged as main problem in the anti-cancer therapy with cytostatically active agents. Classical as well as recently developed cytostatics develop the phenomenon of loosing activity in former drug-sensitive cells. Although MDR is a multifactorial process, the main obstacle is the expression of multidrug-efflux pumps that lowers the intracellular drug levels. P-glycoprotein (P-gp) is the longest identified efflux pump. As the attempt to overcome MDR by the use of inhibitors of the efflux pump activities turned out as most promising effect, the development of P-gp inhibitors has been a challenge for medicinal chemists. The article reviews the advances in P-gp inhibitor development by focussing on structure-activity relationships in the different compound classes to document improvements. The success has been the reduction of cytotoxic properties. The undesired activities could be much lowered in the case of compound classes that were derived from pharmacologically active drugs. Undesired drug interactions and limited in vivo activities are still a problem.