World population growth and modernization have engendered multiple environmental problems: the propagation of humans and crop diseases and the development of multi-drug-resistant fungi, bacteria and viruses. Thus, a considerable shift towards eco-friendly products has been seen in medicine, pharmacy, agriculture and several other vital sectors. Nowadays, studies on endophytic fungi and their biotechnological potentials are in high demand due to their substantial, cost-effective and eco-friendly contributions in the discovery of an array of secondary metabolites. For this review, we provide a brief overview of plant–endophytic fungi interactions and we also state the history of the discovery of the untapped potentialities of fungal secondary metabolites. Then, we highlight the huge importance of the discovered metabolites and their versatile applications in several vital fields including medicine, pharmacy, agriculture, industry and bioremediation. We then focus on the challenges and on the possible methods and techniques that can be used to help in the discovery of novel secondary metabolites. The latter range from endophytic selection and culture media optimization to more in-depth strategies such as omics, ribosome engineering and epigenetic remodeling.