Even if rodents allowed major breakthroughs for biomedical research, a striking issue in modern biology is certainly some failure of studies in mice and rats to be replicated or translated to humans. With the advent of new genome editing techniques such as CRISPR/Cas9, it has become quicker and cheaper to generate a panel of mutations, lot easier to generate more complex models and possible to target different backgrounds in rodents. This speech will discuss possible strategies that are now available thank to CRISPR/Cas9 mediated genome editing to develop better animal models of human disease. We will present our results for generating complex mouse or rat models. We developed the CRISpr Mediated REarrangement (CRISMERE) strategy, which takes advantage of the CRISPR/Cas9 system, to generate easily most of the desired structural variant & CNV rearrangements. We were indeed able to achieve deletions, duplications, and inversions of genomic regions as large as 24.4 Mb in rat and mouse (the good). We will also present how we can combine CRISPR and ES cells to achieve whole gene humanization. Finally, we will show that very careful validation of the lines generated by CRISPR/Cas9 is requested (the bad) and how some unexpected event can be used to generate targeted overexpressing models.