Over the past seven decades, particularly since the discovery of the first marine-derived nucleosides, spongothymidine and spongouridine, from the Caribbean sponge Cryptotethya crypta in the early 1950s, marine natural products have emerged as unique, renewable and yet under-investigated pools for discovery of new drug leads with distinct structural features, and myriad interesting biological activities. Marine sponges are the most primitive and simplest multicellular animals, with approximately 8900 known described species, although more than 15,000 species are thought to exist worldwide today. These marine organisms potentially represent the richest pipeline for novel drug leads. Mycale (Arenochalina) and Clathria are recognized marine sponge genera belonging to the order Poecilosclerida, whereas Biemna was more recently reclassified, based on molecular genetics, as a new order Biemnida. Together, these sponge genera contribute to the production of physiologically active molecular entities with diverse structural features and a wide range of medicinal and therapeutic potentialities. In this review, we provide a comprehensive insight and up-to-date literature survey over the period of 1976–2018, focusing on the chemistry of the isolated compounds from members of these three genera, as well as their biological and pharmacological activities, whenever available