Mosaic variants are by definition present in just some of the cells that make up a given tissue. The frequency of such mosaic variants in that cell population depends on many factors, including when they originated during development, and whether they affect rates or patterns of cellular proliferation or are subject to selection of the cells carrying them. Their confident detection depends on combinations of the following four factors: (1) frequency, type, and functional effect of a mosaic variant; (2) strategy utilized for the discovery (single cell or bulk analyses); (3) applied experimental and analytical method (e.g., sequencing, droplet digital PCR); and (4) funds and effort that can be invested into each experiment. Furthermore, none of the existing strategies and techniques are universally applicable, nor cost effective, to find variants of all types. Studies aimed at discovering mosaic variants should carefully balance strategy, experimental and computational techniques, funds, and effort to carry out experiments and analyses that will allow the aims to be achieved.