With an increasing number of cell-based therapies obtaining marketing authorization in the EU, the availability of an adequate quantity and quality of target cells for use as starting material has emerged as an important issue. Cellular starting materials exhibit variability, which has an impact on downstream processing and final product quality. On the one hand, accommodation of the variability of cell starting materials is usually essential to allow widespread patient access to innovative and life-saving therapies. On the other hand, variability in the starting material can result in inconsistent quality of the final product and failure to meet desired specifications. In this commentary, we critically review factors contributing to cell starting material variability and provide a regulatory perspective on its management.