Members of the genus Trichoderma are a well-established and studied group of fungi, mainly due to their efficient protein production capabilities and their biocontrol activities. Despite the immense interest in the use of different members of this species as biopesticides and biofertilizers, the study of their active metabolites and their biosynthetic gene clusters has not gained significant attention until recently. Here we review the challenges and opportunities in exploiting the full potential of Trichoderma spp. for the production of natural products and new metabolic engineering strategies used to overcome some of these challenges.