Awarded with the 2018 Prose Award in Clinical Medicine, the third edition of Principles of Gender-Specific Medicine explored and described exciting new areas in biomedicine that integrated technology into the treatment of disease and the augmentation of human function. Novel topics such as the sex-specific aspects of space medicine, the development and the use of genderized robots and a discussion of cyborgs were included in the third edition, providing a preview of the expanding world of sex-specific physiology and therapeutics. This Fourth Edition is a continuation of the mission to trace the relevance of biological sex to normal function and to the experience of disease in humans. We are now twenty years into the postgenomic era. The investigation of how the genome produces the phenome has led to fascinating insights as well as yet unanswered questions. Principles of Gender-Specific Medicine, Fourth Edition, has a central theme: discuss advances in understanding the role of epigenetics in regulating gene expression in a dynamic, sex-specific way during human life. It explores the protean role of epigenetics in human physiology, the relevance of environmental experience to human function, the therapeutic promise of cutting-edge methodologies like gene manipulation, the preparation of humans for space travel, the use of artificial intelligence in detection and therapeutic decisions concerning disease states, the possibilities for technological support of not only compromised individuals but of the augmentation of human function, and an analysis of the benefits, limitations and issues that surround our current expectations of personalized medicine.