Since more than 50 years, sponges have raised the interest of natural product chemists due to the presence of structurally original secondary metabolites. While the main objective were first to discover new drugs from the Sea, a large number of interrogations arose along with the isolation and structure elucidations of a wide array of original architectures and new families of natural products not found in the terrestrial environment. In this chapter, we focus on the results obtained during this period on the following questions. A preliminary but still unresolved issue to be addressed will be linked to the role of the microbiota into the biosynthesis of these low-weight compounds. Our knowledge on the biosynthetic pathways leading to plant secondary metabolites is now well established, and this background will influence our comprehension of the biosynthetic events occurring in a sponge. But is the level of similarity between both metabolisms so important? We clearly need more experimental data to better assess this issue. This question is of fundamental interest because sponges have a long evolutionary history, and this will allow a better understanding on the transfer of the genetic information corresponding to the biosynthesis of secondary metabolites. After the how, the why! The question of the ecological role of these metabolites is also of high importance first not only because they can serve as synapomorphic characters but also because they may represent chemical cues in the water environment. Even if most of these compounds are considered as defensive weapons for these sessile invertebrates, they may also be linked to physiological characters as the reproduction. Finally, a metabolomic approach can appear as a complementary tool to give additional information on the sponge fitness. All the new developments in molecular biology and bioanalytical tools will open the way for a better comprehension on the complex field of sponge secondary metabolites.