Short-lived nature – Before gene therapy can become a permanent cure for a condition, the therapeutic DNA introduced into target cells must remain functional & the cells containing the therapeutic DNA must be stable. Problems with integrating therapeutic DNA into the genome & the rapidly dividing nature of many cells prevent it from achieving long-term benefits. Patients require multiple treatments.

Immune response – Any time a foreign object is introduced into human tissues, the immune system is stimulated to attack the invader. Stimulating the immune system in a way that reduces gene therapy effectiveness is possible.

Multigene disorders – Some commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis, & diabetes, are affected by variations in multiple genes, which complicate gene therapy.

Some therapies may breach the Weismann barrier (between soma and germ-line) protecting the testes, potentially modifying the germline, falling afoul of regulations in countries that prohibit the latter practice.