Understanding the physiological contribution of genes requires the use of model systems. The mouse model has given us many insights into disease-causing effects due to the relative ease at which the genome can be modified. We continue to expand our ability to alter the genetic landscape of mice with ever developing techniques and technology. In this talk, I will highlight specifically how we have unraveled the contribution of senescent cells to disease pathology, with a focus on neurodegenerative diseases. Senescent cells, which are stably growth arrested, were believed to be an in vitro phenomenon before the use of mouse models revealed the important effects of these cells to pathology. Vignettes for how we are modifying the genomes of mice to study this disease will be discussed. The intention is to describe the novel approaches to engineer mice that we are employing that would be applicable to any researcher interested in studying the biological contribution of target genes.