Due to their high stability and accumulation over time, translocations are currently the cytogenetic marker of choice for radiation dose estimation following protracted radiation overexposures or overexposures that occurred up to several decades in the past (environmental/occupational/medical exposures). In the course of this, particular intention is focused on the quantification of low doses (≪ 1.0 Gy) for the purpose of evaluating potential associations between different radiation-induced chromosomal aberrations and future health impairments, usually cancer. However, existing limitations of FISH-based translocation analysis give occasion to further optimize this method. In particular, the practical and technical aspects of the method offer a great scope for potential improvements considerably facilitating the performance of extensive studies. On the one hand, huge studies encompassing a considerable number of different collectives aiming at the determination of spontaneous translocation frequencies due to several already determined and potentially not yet known confounders are essential for improved individual dosimetry in the very low dose range. An accurate and reliable individual dosimetry and the methodical feasibility of extensive FISH-based studies are prerequisites to further elucidate the characteristics of radiation induced cancer; e.g., radiation and radiation quality specificity or total dose and dose rate dependencies. This paper focuses on the practical and technical limitations of FISH-based translocation analysis, in fact the tremendous workload and costs of huge approaches, and points out how this could be overcome by method optimization, namely standardizing and automating translocation scoring to allow sharing of future work and planning of more extensive studies.