Ferns have been exposed to herbivorous insects since the latter evolved in the Devonian. Currently, ferns suffer similar percentages of leaf herbivory as angiosperms. Therefore, they often use a combination of chemical defenses as protection against herbivores. In this review, we summarize the distribution of five groups of biomolecules that may act as chemical defenses of ferns: phytoecdysteroids, flavonoids, thiaminase, cyanogenic glycosides, and alkaloids. For each of these biomolecules, we briefly discuss their biosynthesis, mode of action, and currently known taxonomic distribution in ferns, and include examples to illustrate their observed concentrations in different fern tissues. We conclude with a discussion of ferns that accumulate heavy metals, which may also serve in their defense against herbivores. Finally, we discuss research gaps to encourage future research in this widely understudied and ecologically important field of investigation.