Polycyclic tetramate macrolactams (PTMs), a widely distributed class of structurally complex natural products exhibiting diverse biological activities, share a tetramate-containing macrocyclic lactam ring fused to a subset of carbocyclic rings. More than 30 naturally occurring PTM members have been reported. Representative members include ikarugamycin, HSAF, and alteramides. The emerging significance of PTMs in medicinal applications has raised attentions on their biosynthetic studies. These studies have unveiled the unexpected conservation of compact PTM biosynthetic loci in phylogenetically diverse bacteria and elucidated mechanisms for key steps in PTM biosynthesis. PTMs were demonstrated to be derived from the common origin of a hybrid polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) pathway, in which the PKS portion was iteratively used to generate two separate polyketide chains. A common tetramate-containing polyene intermediate was proposed to be the final product of all PTM PKS/NRPS assembly lines. Subsequently, a set of oxidoreductases acted in a not yet clearly understood way to dictate the manner of cyclizations to yield different polycycle ring systems in PTMs. The only well studied example was the formation of the inner fivemembered ring in ikarugamycin, which was catalyzed by an alcohol dehydrogenase via a [1 + 6] Michael addition. Nonetheless, these studies have illustrated the extraordinary simplicity of nature's art in the biosynthesis of PTMs with complex structures and paved the way to further expand the structural diversity of the family of medicinally relevant PTMs by genome mining and combinatorial biosynthesis.