The discovery of new natural products for drug development greatly depends on rich biodiversity, with the marine environment serving as a prime example. Research into marine natural products has led to the development of several clinical drugs and numerous other candidates, some of which are currently undergoing clinical trials. The marine megadiversity of Papua New Guinea represents a vast, yet largely untapped, source of bioactive natural products. In this review, highlighted are a selection of structurally unique natural products derived from PNG sponges and filamentous cyanobacteria, focusing on those with promising biological activity and potential for drug development. Many of the sponge-derived bioactive compounds presented here appear to originate from non-ribosomal peptide and polyketide biosynthesis pathways, indicating a likely microbial origin. It is through international collaborative efforts, with funding support from programmes, such as the Papua New Guinea International Cooperative Biodiversity Groups (ICBGs), the National Cooperative Drug Discovery Program Group (NCDDG), the Natural Sciences and Engineering Research Council of Canada, the Canadian Cancer Society and others that these bioactive molecules were discovered.