Exploring the minimal genetic requirements for cells to maintain free living is an exciting topic in biology. Multiple approaches are employed to address the question of the minimal genome. In addition to constructing the synthetic genome in the test tube, reducing the size of the wild-type genome is a practical approach for obtaining the essential genomic sequence for living cells. The well-studied has been used as a model organism for genome reduction owing to its fast growth and easy manipulation. Extensive studies have reported how to reduce the bacterial genome and the collections of genomic disturbed strains acquired, which were sufficiently reviewed previously. However, the common issue of growth decrease caused by genetic disturbance remains largely unaddressed. This mini-review discusses the considerable efforts made to improve growth fitness, which was decreased due to genome reduction. The proposal and perspective are clarified for further accumulated genetic deletion to minimise the genome in terms of genome reduction, experimental evolution, medium optimization, and machine learning.