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The definition of the Target Volumes has evolved with time. In 1978, ICRU #29 defined for the first time the term “Target Volume” combining both the macroscopic disease and its microscopic extension. In the subsequent ICRU reports #50 (1993) and #62 (1999), a distinction was introduced between the GTV for the Gross (visible or palpable) Tumor Volume and the CTV for Clinical Target Volume encompassing both the macroscopic (if any) and the microscopic tumor burden. More recently, the ICRU report #83 (2010) summarised the practical implementation of these concepts in the 3D imaging configuration. However, the CTV was still defined as a finite volume typically encompassing anatomic compartments in which a given amount of cancer cells was thought to be homogeneously distributed. In 2020, we now have evidences that neither the GTV nor the CTV are homogenous structures, but rather are volumes with an heterogenous distribution of target cell (stem cells) densities. Molecular imaging with PET or MRI can clearly depict the heterogeneous nature of GTV. For various tumor types such as head and neck, lung, brain and prostate, three-dimentional pathological examination of surgical specimens have also identified that microscopic cell density typically decreases as a function of the distance from the border of the GTV; such distance varies according to the histologic types and the organ in which tumor developed. Altogether, these data should prompt the clinicians to revisit the practical implementation of the target volume concept to better integrate the notion of probability of target cells presence within the complex anatomic compartments surrounding the GTV. The identification of such heterogeneous tumor cell distribution, could serve as the basis for varying dose prescription.