Specialized metabolites correspond to millions of natural molecules from different chemical families depending on plant taxa that play a key role in ecological interactions during their life cycle. Due to their chemical properties, plants’ specialized metabolites have been exploited for a long time for various industrial applications. However, the limitations in natural population resources as well as the difficulties of their cultivation in terms of production quality or product safety have not always been satisfactory, notably for perennials such as forest trees. Reliable and eco-adapted practices for the production of specialized metabolites such as in vitro cultures provide a useful and powerful alternative to agronomic cultures. Modern omics have allowed the identification of metabolite pathways but have also raised the question of their complex regulation to improve their production. Among the major regulatory players, epigenetics have been shown in recent years to be involved in plant development and the response to environmental variations. Here, the state of the art concerning the epigenetic control of plant specialized metabolite in vitro production as well as the challenges in forest trees are presented.