Purpose Oocyte activation is a fundamental event at mammalian fertilization. In mammals, this process is initiated by a series of characteristic calcium (Ca2+) oscillations, induced by a sperm-specific phospholipase C (PLC) termed PLCzeta (PLC zeta). Dysfunction/reduction/deletion of PLC zeta is associated with forms of male infertility where the sperm is unable to initiate Ca2+ oscillations and oocyte activation, specifically in cases of fertilization failure. This review article aims to systematically summarize recent advancements and controversies in the field to update expanding clinical associations between PLC zeta and various male factor conditions. This article also discusses how such associations may potentially underlie defective embryogenesis and recurrent implantation failure following fertility treatments, alongside potential diagnostic and therapeutic PLC zeta approaches, aiming to direct future research efforts to utilize such knowledge clinically. Methods An extensive literature search was performed using literature databases (PubMed/MEDLINE/Web of Knowledge) focusing on phospholipase C zeta (PLCzeta; PLC zeta), oocyte activation, and calcium oscillations, as well as specific male factor conditions. Results and discussion Defective PLC zeta or PLC zeta-induced Ca2+ release can be linked to multiple forms of male infertility including abnormal sperm parameters and morphology, sperm DNA fragmentation and oxidation, and abnormal embryogenesis/pregnancies. Such sperm exhibit absent/reduced levels, and abnormal localization patterns of PLC zeta within the sperm head. Conclusions Defective PLC zeta and abnormal patterns of Ca2+ release are increasingly suspected a significant causative factor underlying abnormalities or insufficiencies in Ca2+ oscillation-driven early embryogenic events. Such cases could potentially strongly benefit from relevant therapeutic and diagnostic applications of PLC zeta, or even alternative mechanisms, following further focused research efforts.