Interactions between the sperm-borne oocyte activating factor(s) (SOAF) and the molecules within the oocyte cytoplasm, trigger the molecular pathways associated with oocyte activation. Of note, release of calcium from the endoplasmic reticulum (ER) creates calcium oscillations in mammals and one large calcium release in non-mammalian species. As the newly activated ovum begins to transform, the components of the fertilizing spermatozoon function cooperatively with the contents of the ooplasm as development progresses. The spermatozoon has been shown to contribute the main microtubule framework to the embryo through the integration of its centriole and has also been implicated in facilitating processes. Through oocyte-driven mechanisms, unnecessary sperm components must also be degraded. Many of these processes are centered around the reducing power of oocyte-produced glutathione (GSH) and facilitated by both the sperm-borne and oocyte-borne enzymatic activity. In this chapter we explore underlying molecular and biochemical processes that drive developmental progression of newly fertilized oocytes, and how ICSI procedures could change the molecular pathways found in natural fertilization.