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Single-pass transmembrane proteins (TM1) are a diverse group of proteins characterised by a single transmembrane domain. In total, the authors found approximately 1300 TM1 proteins in the human genome, most of which have characterised functions. The extracellular domains of these proteins range up to 22 000 amino acids with an average size being six times larger than intracellular domains. This suggests that these proteins have evolved the capacity to bind a wide array of ligands and substrates. Consequently, these proteins are involved in many processes, such as adhesion, migration, growth and cell death, among others. Although many act as receptors for first messengers (extracellular signalling molecules), they can also serve as ligands, adaptors, proteases and coreceptors. Herein, the authors provide a broad overview of these different roles along with examples of their involvement in pathological and physiological situations. Key Concepts: Single-pass transmembrane proteins participate in signalling in a variety of ways, either as ligands, receptors, enzymes coreceptors and/or adaptors. TM1 proteins appear to have undergone evolutionary expansion as a function of body plan complexity. The extracellular domains of TM1 proteins cluster well based on family, whereas the intracellular domains do not. TM1 proteins are adapted to bind very large substrates/ligands compared with other receptor families (ion channels and GPCRs). TM1 have roles in every organ system and are particularly important in the immune and nervous systems. Keywords: signal transduction; single-pass transmembrane proteins; receptor tyrosine kinase; type-1 single pass transmembrane protein; proteases; axon guidance; immune signalling; cell adhesion