This paper presents a review of 12 patients with a G/G translocation and suggests that trisomy of the band 21q22 may be pathogenetic in Down's syndrome. In 1963, Zellweger et al. described a child with Down's syndrome and a tandem translocation. Since then, 13 similar cases have been reported, including two familial cases. A 2-year-old boy with typical Down's syndrome features was studied and found to have a tandem translocation between the long arms of two chromosomes No. 21. Subterminal heterochromatin blocks and satellites were observed, indicating breaks distally at the long arm of both chromosomes. Fluorescence studies and the size of the translocation suggested minimal loss of chromosomal material. The case is not unique, as other authors have demonstrated the specific translocation type. The paper proposes that trisomy of a limited segment on chromosome No. 21 is essential for the development of typical Down's syndrome features. This hypothesis is based on observations: 1. Patients with G/G translocations show clinical variability. 2. The presence of satellites and new staining techniques indicate that the translocation chromosome is formed by breaks distally on both chromosomes. 3. None of the abnormal chromosomes show loss exceeding one third of the total long arm length of chromosome No. 21. 4. Patients with Down's syndrome due to Robertsonian translocations and free trisomy are phenotypically identical. These observations suggest that the clinical features are due to varying amounts of loss distally at the long arm of chromosome No. 21, and that trisomy of the very distal segment (21q22) may be pathogenetic in Down's syndrome. Further support for this hypothesis may be obtained by applying new staining techniques to similar cases.This paper presents a review of 12 patients with a G/G translocation and suggests that trisomy of the band 21q22 may be pathogenetic in Down's syndrome. In 1963, Zellweger et al. described a child with Down's syndrome and a tandem translocation. Since then, 13 similar cases have been reported, including two familial cases. A 2-year-old boy with typical Down's syndrome features was studied and found to have a tandem translocation between the long arms of two chromosomes No. 21. Subterminal heterochromatin blocks and satellites were observed, indicating breaks distally at the long arm of both chromosomes. Fluorescence studies and the size of the translocation suggested minimal loss of chromosomal material. The case is not unique, as other authors have demonstrated the specific translocation type. The paper proposes that trisomy of a limited segment on chromosome No. 21 is essential for the development of typical Down's syndrome features. This hypothesis is based on observations: 1. Patients with G/G translocations show clinical variability. 2. The presence of satellites and new staining techniques indicate that the translocation chromosome is formed by breaks distally on both chromosomes. 3. None of the abnormal chromosomes show loss exceeding one third of the total long arm length of chromosome No. 21. 4. Patients with Down's syndrome due to Robertsonian translocations and free trisomy are phenotypically identical. These observations suggest that the clinical features are due to varying amounts of loss distally at the long arm of chromosome No. 21, and that trisomy of the very distal segment (21q22) may be pathogenetic in Down's syndrome. Further support for this hypothesis may be obtained by applying new staining techniques to similar cases.