Actinomycetes are known for their unprecedented ability to produce novel lead compounds of clinical and pharmaceutical importance. This review focuses on the diversity, abundance and methodological approaches targeting marine sponge-associated actinomycetes. Additionally, novel qPCR data on actinomycete abundances in different sponge species and other environmental sources are presented. The natural products literature is covered, and we are here reporting on their chemical structures, their biological activities, as well as the source organisms from which they were isolated.