Purpose: Motile sperm organelle morphology examination (MSOME) is a real-time high magnification motile sperm examination applied prior to intracytoplasmic morphologically selected sperm injection (IMSI) - intracytoplasmic injection of the selected spermatozoon. Over the past decade, there is an important shift concerning MSOME, focusing on the shape of the sperm head and presence of vacuoles, resulting with different selection criteria. The authors investigated the relevance of sperm vacuoles phenomenon. From a clinical perspective they focused on prospective trials aiming to distinguish scenarios in which IMSI may improve clinical outcome compared with intracytoplasmic sperm injection (ICSI). Materials and Methods: The authors performed this review based on a primary literature search of publications, which as of November 1, 2017, were listed in PubMed under the search phrase <motile-sperm organelle morphology examination>, <MSOME>, <intra-cytoplasmic morphologically selected sperm injection>, <IMSI>, and <sperm vacuoles>. The references of these manuscripts were further reviewed when considered relevant to the subject. Results: Inadequate chromatin compaction leads to higher rate of DNA fragmentation and aneuploidies, which may be followed by the appearance of large vacuoles. Distinguishing between large and small vacuoles remains a challenge. IMSI may expand blastocyst formation in cases of previous embryos developmental arrest and may be used in cases of isolated teratospermia and repetitive ICSI cycles failures. Conclusions: Solid evidence supports the association between non-adequate sperm DNA compaction and DNA defects, resulting with abnormal vacuoles. Current prospective studies emphasize ICSI as first treatment for male factor during assisted reproductive technology (ART), while the role of IMSI in selective clinical scenarios warrants further large randomized controlled studies.