Human disease is rarely a matter of all or nothing; variable expressivity is generally observed. Part of this variability is explained by somatic mosaicism, which can arise by a myriad of genetic alterations. These can take place at any stage of development, possibly leading to unusual features visible at birth, but can also occur later in life, conceivably leading to cancer. Previously, detection of somatic mosaicism was extremely challenging, as many gold standard tests lacked the necessary resolution. However, with the advances in high-throughput sequencing, mosaicism is being detected more frequently and at lower levels. This raises the issue of normal variation within each individual vs mosaicism leading to disease, and how to distinguish between the two. In this article, we will define somatic mosaicism with a brief overview of its main mechanisms in concrete clinical examples, discuss the impact of next-generation sequencing technologies in its detection, and expand on the clinical implications associated with a discovery of somatic mosaicism in the clinic.