Mammalian spermatozoa are highly complex specialized cells that survive a long and fascinating journey from the site of insemination to the upper third of the oviduct, where fertilization occurs. During this journey, these cells have to go through different microenvironments, which provide appropriate conditions for the occurrence of sperm capacitation and acrosome reaction (AR) in the time and place needed. These events need to occur in an extremely synchronized sequence in order to assure that fertilization takes place. The objective of this review article is to describe and analyze the various changes that spermatozoa will experience during their journey through the female genital tract and how they are influenced by the epithelium and secretions present in the cervix, endometrium and oviduct. These microenvironments will prevent the AR from occurring ahead of time as in the case of estrogenic cervical mucus or will stimulate its occurrence as in the case of progesterone, present during ovulation in oviductal fluid. In all cases the female reproductive tract will supply the conditions needed to guarantee survival, capacitation, AR and migration of spermatozoa for subsequent fusion with the oocyte. These microenvironments contain various hormones, neurotransmitters and other metabolites for which spermatozoa have specific receptors through which these substances can modulate their fertilizing potential. The study and understanding of the physiological conditions needed for gamete membrane fusion to occur is an important aspect to be considered both in basic and applied research in reproductive biology.