Systemic isotretinoin treatment (SI) has become a revolutionary drug treatment for various, mostly severe, forms of acne. Despite the relatively long history of its use, controversy continues concerning the dosing regimens. Their flexibility is most often considered a factor in minimizing the undesirable effects of hypervitaminosis A. The more information that become available about the mechanisms of the effect SI, the greater the list of diseases for which a possible positive effect can be expected from the treatment. In the article, on the basis of scientific data and clinical experience, the mechanisms for implementing the anti-relapse effect of SI are explained. The positions of the drug in the classifications of retinoids and the ways of its biological action are also presented; the factors affecting its implementation are described. Of great interest are the interreceptor interactions of various types of retinoid receptors with other groups of nuclear receptors that affect drug activity. It has been suggested that the anti-tumor effect of retinoids, and the mechanisms of its implementation, are related to the anti-relapse effect in severe forms of acne, and that this explains why this effect does not increase in moderate forms of the disease. The proposed explanations may be applicable in the treatment of other retinoid-sensitive dermatoses. Solving the problem of bioavailability using micronization mechanisms and improving the delivery of systemic isotretinoin treatment would have a positive effect on the efficacy and safety of the drug, and allow for a reduction in both its daily and course dose.