Fish, like all other animals, are exposed to constant contact with microbes, both on their skin and on the surfaces of their respiratory and digestive systems. Fish have a system of non-specific immune responses that provides them with initial protection against infection and allows them to survive under normal conditions despite the presence of these potential invaders. However, fish are less protected against invading diseases than other marine vertebrates because their epidermal surface, composed primarily of living cells, lacks the keratinized skin that serves as an efficient natural barrier in other marine vertebrates. Antimicrobial peptides (AMPs) are one type of innate immune protection present in all life forms. AMPs have been shown to have a broader range of biological effects than conventional antibiotics, including antibacterial, antiviral, antiprotozoal, and antifungal effects. Although other AMPs, such as defensins and hepcidins, are found in all vertebrates and are relatively well conserved, piscidins are found exclusively in Teleost fish and are not found in any other animal. Therefore, there is less information on the expression and bioactivity of piscidins than on other AMPs. Piscidins are highly effective against Gram-positive and Gram-negative bacteria that cause disease in fish and humans and have the potential to be used as pharmacological anti-infectives in biomedicine and aquaculture. To better understand the potential benefits and limitations of using these peptides as therapeutic agents, we are conducting a comprehensive study of the Teleost piscidins included in the “reviewed” category of the UniProt database using bioinformatics tools. They all have amphipathic alpha-helical structures. The amphipathic architecture of piscidin peptides and positively charged residues influence their antibacterial activity. These alpha-helices are intriguing antimicrobial drugs due to their stability in high-salt and metal environments. New treatments for multidrug-resistant bacteria, cancer, and inflammation may be inspired by piscidin peptides.