A calcium signal during oocyte or egg activation is a conserved event in virtually all species analyzed so far. This signal, that is in the form of calcium oscillations in mammals, is spatially and temporally controlled and is mainly supported by calcium release from internal calcium stores, but how it is triggered after fertilization is far from understood. The sperm factor hypothesis of egg activation postulates that sperm delivers a calcium-releasing factor into the egg following sperm-egg fusion. Among the many potential sperm factors, PLCzeta is the strongest bona fide sperm factor candidate. However, how sperm-oocyte fusion occurs prior to PLCzeta delivery and oocyte activation is not entirely known. We propose in the first part of this review the possibility that other pathways such as those involving G-proteins, tyrosine kinases or integrins could be activated besides sperm factor injection and could be upstream mechanisms involved in later embryonic development. Among different assisted reproductive technologies (ARTs), intracytoplasmic sperm injection (ICSI) is considered as the best and easiest therapeutic technique to circumvent severe male infertility. Although most reports are reassuring, some recent data suggest a greater incidence of abnormalities in children conceived by ART compared with those conceived normally. Spatio-temporal signals may be missing or abnormal during ICSI, perhaps because membrane fusion and signalling events are bypassed. We discuss in the second part of this review the hypothesis that potential perturbations during the ICSI procedure may have repercussions on epigenetic processes, inducing not only alterations of embryonic development, but also diseases in young children and, perhaps, in adults.