Transgenic animals – worms, flies, fishes, rodents and livestock – are the invaluable models that have allowed the scientific and medical community to study in depth the mechanisms of gene and genome function and complex disease phenotypes, to discover current and potential therapeutic approaches. The first section of this book discusses advantages, limitations, pitfalls and applications of the powerful genome modification technologies such as Zinc-finger nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), CRISPR-Cas systems, the Cre/loxP binary systems, and lentiviral transduction, which made possible to generate transgenic organisms in a more efficient way, introduced a new era in gene function and cellular physiology analysis, and opened new perspectives for biomedical research. The optimized techniques such as somatic cell nuclear transfer and cytoplasmic injection of exogenous DNA into zygotes are also the promising tools to generate transgenic livestock with special traits. A systematic overview on induced pluripotent stem cells (iPSC) generation and the applicative potential in the most important mammalian farm animal species is presented. The remaining content of this book focuses on the animal models of Duchenne muscular dystrophy, aging, protein-misfolding diseases, neurodegenerative diseases, congenital diseases, psychiatric disorders, motor neuron disorders, cancer, immunodeficiency disease, ribosomopathies, and RASopathies among others. The possible future directions and unresolved challenges are outlined.