Human molecular cytogenetics integrates the knowledge on chromosome and genome organization at the molecular and cellular levels in health and disease. Molecular cytogenetic diagnosis is an integral part of current genomic medicine and is the standard of care in medical genetics and cytogenetics, reproductive medicine, pediatrics, neuropsychiatry and oncology. Regardless numerous advances in this field made throughout the last two decades, researchers and practitioners who apply molecular cytogenetic techniques may encounter several problems that are extremely difficult to solve. One of them is undoubtedly the occurrence of somatic genome and chromosome variations, leading to genomic and chromosomal mosaicism, which are related but not limited to technological and evaluative limitations as well as multiplicity of interpretations. More dramatically, current biomedical literature almost lacks descriptions, guidelines or solutions of these problems. The present article overviews all these problems and gathers those exclusive data acquired from studies of genome and chromosome instability that is relevant to identification and interpretations of this fairly common cause of somatic genomic variations and chromosomal mosaicism. Although the way to define pathogenic value of all the intercellular variations of the human genome is far from being completely understood, it is possible to propose recommendations on molecular cytogenetic diagnosis and management of somatic genome variations in clinical population.