Unbalanced chromosomal abnormalities are associated with alteration of the gene dosage, with subsequent disruption of normal chromatin contact patterns and genomic regulation. Chromosome therapy has been proposed as a therapeutic intervention for amending various chromosomal aberrations. Numerous methods have been erupted where the goal was to eliminate the effects of the altered gene dosage. This could be achieved through removal or silencing the extrachromosomal material from the cells in cases of different syndromic trisomes and chromosomal duplications or to replace the deleted genetic material in cases of pure deletion either terminal deletion or that leads to ring chromosome formation. There are also different proposed ideas to comprise other structural abnormalities within the targets of chromosome therapy. Very recently, research studies on chromosome transplantation have been presented aiming to deal with various X-linked disorders as well as different structural chromosomal abnormalities. It is remarkable that several concepts of the proposed designs are either inspired or explained from naturally existing mechanisms for adjusting cell cycle, for example, using X-Inactivation Specific Transcript gene for silencing the added chromosome, uniparental disomy, and trisomy rescue. Although all studied strategies are still at the cellular level, the results of these studies will unravel different complex interacting pathways between multiple deleted or duplicated genes and identifying appropriate targets for therapeutic interventions. Current clinical application is confronted by certain obstacles, including ethical and technical limitations. As most of the proposed strategies for chromosome therapy have to be performed on continuously dividing cells and ethical considerations impede germline intervention, hence, at this stage, chromosome therapy can only be considered as a plausible therapeutic strategy for somatic, actively dividing cells.