Selective use of crude plant extracts has been the oldest ritual in ancient Indian Medicinal System ‘Ayurveda’, as well as in Traditional Chinese Medicine system for thousands of years. This has been well documented that herbal medicines of Chinese, Indian, Korean and Native American people had included bryophytes, lichens, lycophytes and ferns. Since antiquity, most of the ferns and fern allies have given many health benefits to ancient civilizations who had used them for food, tea and drugs. Modern approaches have combined multidisciplinary technologies and have specific chemical compounds extracted and identified for producing very particulate medicines from plant parts. Plants, which yield appreciable quality and quantity of polysaccharides, steroids, terpenoids, flavonoids, alkaloids and antibiotics are suitable for dragging out drugs for many ailments/diseases, including cancer treatments. Modern explorations on the functional activities of pteridophytes for human health by discovering specific compounds and their usage in medicines have widened the scope of pteridophytes by shaping these plants as a great boon for pharmaceutical companies and related industries. Even ‘fern weeds’, which invade our freshwater bodies and reduce the freshwater wealth of a lake, e.g. Azolla, Salvinia, Marsilea, Ceratopteris, etc. can be utilized to produce life saving drugs because they are reservoirs of very many organic compounds that are useful as medicines. Some of the fern genera have a few unique secondary metabolites, which have not been discovered in higher plants. Polyphenols are useful phytochemicals, which provide health benefits such as antioxidants. From experiments on screening of total polyphenol contents of 37 ferns and fern allies, Polystichum lepidocaulon and Polystichum polyblepharum were reported to have more than 13% of total polyphenols from dried materials of both fronds and rhizomes. In addition, fronds of Davallia mariesii and rhizomes of Cyrtomium fortune, Dicranopteris pedata, Athyrium niponicum and Dryopteris nipponensis showed more than 10% of total polyphenols from dried materials. High bioactivities of traditional medicinal ferns have been studied internationally to underscore their roles in medicine. These attempts have confirmed various bioactivities, such as antioxidant, antimicrobial, antiviral, anti-inflammatory, antitumor and anti-HIV, etc. The occurrence of antibiotic activity in the extracts of more than 200 species of pteridophytes has been shown to be of prime significance within the period of 1975–2015. The active substances in many cases were found to be antibacterial to penicillin-resistant Staphylococcus aureus, Mycobacterium phlei, Salmonella typhi, Vibrio cholera, and Pseudomonas aeruginosa. Dryopteris cochleata was active against both bacteria and fungi. Five other species of Dryopteris showed remarkable antibacterial activity. The ferns of ‘Adiantum group’ have been found to be particularly active against Gram-positive bacteria. The polypodiaceous ferns constitute a rich group of which Microsorum alternifolium, Leptochillus decurrens, Polypodium irioides, Pyrrosia mannii and Phymatodes ebenipes deserve special mention. Several thelypteroid, davallioid and athyrioid ferns, in addition to antibiotic activity have also been found to show most useful bioactivity for our life – the antioxidant activity. The latter superb biochemical quality of ferns alone makes most ferns of great advantage to human health. Lycophytes particularly Lycopodium clavatum and Equisetum hyemale and ferns (Dryopteris and Adiantums) have had constituted the backbone of Homeopathic medicines and now many more genera have been added to the network of modern medicinal approaches in the drug industry. These pteridophytes are indispensably integral parts of forests world over. A few of the aquatic ferns (Azolla, Salvinia) serve as excellent bio-fertilizers and bioremediation agents. Medicinal plants are under cultivation and cultured world over. Botanically, say a thousand years ago, these were wild and many of them were weeds. As pteridophytes have survived since Paleozoic, they have undergone series of disruptive adaptive changes of environment than any other vascular plants. These plants most likely, could withstand the tests of geological time on account of their being guarded with genetic capability of possessing many useful oils, phytochemicals (secondary metabolites) such as flavonoids, steroids, alkaloids, phenols, triterpenoid compounds, varieties of amino acids and fatty acids, which in turn offer inherent tolerance and defense system . Additionally, from evolutionary point of view majority of ferns have constituted carpet flora and have worked as ‘cradles’ in natural forests so as to nurture small animals particularly reptiles and mammals. Ferns are denominators of prevalent rich biodiversity in almost every part of the earth. Comparison of evolutionary adaptations and natural innovations illuminate the genetic basis for the development of organisms. It is emphasized that there should be good field stations just in the peripheral region of reserved forests with large green houses to function as ‘Fernariums/ Mossariums/ and/or Lichenariums’ to conserve and maintain rare, endangered and medicinally superlative species found in those areas/forests. Gene networks (DNA stretches) that retain similar wiring diagrams (some or many similar DNA sequences) among related, distantly related or even totally diverse organisms point to the ways in which regulatory regions of the genome have evolved. Indisputably, comparative genomics can help us in deciphering evolvability of gene network and conservation modes during vast geological journey in evolution. We need exhaustive genomics and multidimensional molecular genetic studies on pteridophytes so as to discover unique DNA sequences, which could turn the gates of modern medicine.