Microbial symbionts of marine sponges have long been suspected as the actual producers of many sponge-derived complex compounds. Since the majority of microbial symbionts are not amenable to cultivation, metagenomic approaches have been developed to identify biosynthetic gene clusters and the responsible symbiotic bacteria, providing genetic evidence for the bacterial origin of many sponge-derived compounds. Recent developments in single-cell genomics combined with new DNA sequencing technologies and bioinformatic tools have enabled the rapid discovery of biosynthetic pathways from as-yet uncultivated symbiotic bacteria. This subsequently offers exciting opportunities to activate “metagenomic” biosynthetic pathways in easily culturable bacteria to sustainably produce rare sponge-derived bioactive compounds. This review describes the biosynthetic aspects of complex bioactive non-ribosomal peptides from uncultivated bacterial symbionts of marine sponges, exemplified by konbamide-type compounds, keramamide-type compounds, and kasumigamide. These interesting non-ribosomal peptides, along with many other sponge-derived peptides, are characterized by the presence of noncanonical amino acids, such as α-ketoamides, thiazole/oxazole, and halogenated amino acids, as parts of their building blocks. Recent development of novel technologies in automated peptide synthesis enables the assembly of non-proteinogenic amino acids to build diverse bioactive peptides with unique properties. We therefore also discuss the pharmaceutical importance and biosynthetic origin of some non-proteinogenic amino acid building blocks of non-ribosomal peptides from sponge symbionts.