Thymus is a primary lymphoid organ essential for the development of T lymphocytes. Age-related thymic involution is a prominent feature of immune senescence. The thymus undergoes rapid growth during fetal and neonatal development, peaks in size before puberty and then begins to undergo a decrease in cellularity with age. Dramatic changes occur with age-associated thymic involution. The most prominent features of thymic involution include: (i) epithelial structure disruption, (ii) adipogenesis, and (iii) thymocyte development arrest. There is a sex disparity in thymus aging. It is a multifactorial process controlled and regulated by a series of molecules, including the transcription factor FOXN1, fibroblast and keratinocyte growth factors (FGF and KGF, respectively), sex steroids, Notch signaling, WNT signaling, and microRNAs. Nevertheless, there is still no satisfactory evolutionary or physiological explanation for age-associated thymic involution, and understanding the precise mechanism(s) for thymus aging remains challenging. Sustained thymic regeneration has yet to be achieved by sex steroid ablation. Recent preclinical studies indicate that long-term thymic reconstitution can be achieved via adoptive transfer of in vitro-generated progenitor T (proT) cells, and improvements in the methods for the generation of human proT cells make this an attractive approach. Future clinical applications may rely on new applications integrating proT cells, cytokine support and sex-steroid inhibition treatments.