G-banded karyotypes (413 in all) of the hypotetraploid mouse myeloma MOPC-21 and five cell lines isolated at different times, of the MOPC-315 tumor and a cell line, and of the X5563 tumor were compared. Two consistent markers and their possible origins were described. In addition to these characteristic myeloma markers, one homolog of chromosome pairs 3, 12, and 15 and one of the Xs may have been altered or lost before tetraploidization occurred. One cell line which had spontaneously become non-oncogenic with time in culture was studied before, during, and after this change. Associated karyotypic changes were: the addition of a large heterochromatic minute and a small marker, one half of which was centromeric heterochromatin; new rearrangements of chromosomes Nos. 3 and 12 and the X; and an apparent increase in immunogenicity of the non-oncogenic cell line.