Uterine leiomyomas represent a major health problem for women in reproductive age, as these benign monoclonal tumors introduce a pathological state in the female reproductive system structure and function. Despite their common clinical occurrence, the etiology of their incidence remains unclear. Several theories have been proposed in an attempt to clarify the etiology and route of tumor formation in leiomyomas, with estrogen/progesterone and several growth factors, cytokines, chemokines, genes and microRNAs to have been implied as key regulators in their growth. The structured theories presented so far indicate multiple candidates or an occurring interplay between these factors, with the reported findings to denote a composite molecular and biological involvement to attribute to the nature of their pathogenesis. Undoubtedly the evolving molecular technologies and recent developments allow a faster assembly of a vast array of data that should ultimately contribute in the establishment of the etiology and the related events leading to leiomyoma formation to ensure a more targeted management and treatment of the affected individuals.