Gene therapy is an evolutionary strategy, and it has become the paradigm of an approach that alters forever our conception of diseases as entities to treat at their genetic source. This chapter provides a brief survey over the various gene therapeutic strategies and their experimental rationales. The distinction between germline vs. patient specific gene disruption; somatic gene therapy lays the foundation for today’s clinical applications. Methods for delivery include both in vivo and ex-vivo, each with their own benefits. Gene addition therapies entail the insertion of functioning copies of genes that are missing or defective, allowing cells to return to normal function. Today’s gene-editing tools—the CRISPR/Cas systems, base editors and prime editors—make it easy to repair harmful mutations directly. Beside direct genome editing, RNA-based approaches comprising antisense oligonucleotides (AO), RNA interference are versatile methods for acting on gene expression at the transcript level. Because these treatments do not actually change the genome for good, they might provide a reversible and tuneable treatment option for many other genetic diseases. New re-engineering methods such as organelles targeted and cell-specific gene therapy increase the precision and decrease off-target events. Together, they have led to a wave of new therapies that includes Luxturna, Zolgensma, Spinraza, and Casgevy. Together with recent advances in delivery systems, gene-editing approaches, and the development of control systems this will likely shift the field from rare monogenic diseases to complex and acquired disorders and lay a path for more personalized therapies based on molecular etiology.