The chapter discusses the development of mucosal vaccines and the role of the mucosal immune system in protecting against microbial pathogens and treating inflammatory disorders. The mucosal immune system, which includes the aerodigestive and urogenital tracts, eye conjunctiva, inner ear, and exocrine gland ducts, is equipped with mechanical and chemical cleansing mechanisms and a specialized innate and adaptive immune response. This system contributes about 80% of all immunocytes in a healthy adult and is organized into mucosa-associated lymphoid tissues (MALT) that form the largest mammalian lymphoid organ system. The mucosal immune system has three main functions: protecting mucosal surfaces from colonization and invasion, preventing the uptake of undegraded antigens, and preventing harmful immune responses to these antigens. The MALT is highly compartmentalized and functions independently from the systemic immune system, with distinct anatomical sites such as Peyer patches, mesenteric lymph nodes, and tonsils serving as primary mucosal inductive sites. Mucosal immune responses are influenced by the nature of antigens, the type of antigen-presenting cells (APCs), and the local microenvironment. Antigens can evoke either TH2 responses leading to oral tolerance or stronger, broader immune responses that do not lead to oral tolerance. The mucosal immune system also maintains tolerance through mechanisms like activation-induced cell death, anergy, and the induction of regulatory T cells (Tregs). Mucosal vaccines are crucial for protecting against infections that affect mucosal surfaces, such as gastrointestinal, respiratory, and sexually transmitted infections. Examples include vaccines against Helicobacter pylori, Vibrio cholerae, and HIV. The primary route of vaccination is often mucosal due to the nature of these infections. However, stimulating strong SIgA responses and protection through mucosal administration has been challenging. Mucosal vaccines for immunotherapy, such as those against autoimmune diseases and allergies, have shown promise. Mucosal tolerance induction through coadministering immunomodulating agents with autoantigens or allergens has been effective in animal models and some clinical trials. Mucosal desensitization, particularly through oral or sublingual administration of allergens, has been successful in treating allergic rhinitis and asthma. The development of effective mucosal vaccines requires efficient antigen delivery systems and adjuvants. Various inert and live bacterial or viral vector systems have been developed, with poxviruses and virus-like particles showing promise. Mucosal adjuvants like detoxified cholera toxin and heat-labile enterotoxin have been studied, with some derivatives being developed for human use. Despite progress, challenges remain in understanding mucosal immune responses in humans, especially in infants and young children, and in developing safe and effective mucosal vaccines for diverse populations.The chapter discusses the development of mucosal vaccines and the role of the mucosal immune system in protecting against microbial pathogens and treating inflammatory disorders. The mucosal immune system, which includes the aerodigestive and urogenital tracts, eye conjunctiva, inner ear, and exocrine gland ducts, is equipped with mechanical and chemical cleansing mechanisms and a specialized innate and adaptive immune response. This system contributes about 80% of all immunocytes in a healthy adult and is organized into mucosa-associated lymphoid tissues (MALT) that form the largest mammalian lymphoid organ system. The mucosal immune system has three main functions: protecting mucosal surfaces from colonization and invasion, preventing the uptake of undegraded antigens, and preventing harmful immune responses to these antigens. The MALT is highly compartmentalized and functions independently from the systemic immune system, with distinct anatomical sites such as Peyer patches, mesenteric lymph nodes, and tonsils serving as primary mucosal inductive sites. Mucosal immune responses are influenced by the nature of antigens, the type of antigen-presenting cells (APCs), and the local microenvironment. Antigens can evoke either TH2 responses leading to oral tolerance or stronger, broader immune responses that do not lead to oral tolerance. The mucosal immune system also maintains tolerance through mechanisms like activation-induced cell death, anergy, and the induction of regulatory T cells (Tregs). Mucosal vaccines are crucial for protecting against infections that affect mucosal surfaces, such as gastrointestinal, respiratory, and sexually transmitted infections. Examples include vaccines against Helicobacter pylori, Vibrio cholerae, and HIV. The primary route of vaccination is often mucosal due to the nature of these infections. However, stimulating strong SIgA responses and protection through mucosal administration has been challenging. Mucosal vaccines for immunotherapy, such as those against autoimmune diseases and allergies, have shown promise. Mucosal tolerance induction through coadministering immunomodulating agents with autoantigens or allergens has been effective in animal models and some clinical trials. Mucosal desensitization, particularly through oral or sublingual administration of allergens, has been successful in treating allergic rhinitis and asthma. The development of effective mucosal vaccines requires efficient antigen delivery systems and adjuvants. Various inert and live bacterial or viral vector systems have been developed, with poxviruses and virus-like particles showing promise. Mucosal adjuvants like detoxified cholera toxin and heat-labile enterotoxin have been studied, with some derivatives being developed for human use. Despite progress, challenges remain in understanding mucosal immune responses in humans, especially in infants and young children, and in developing safe and effective mucosal vaccines for diverse populations.