The most essential function of the immune system relies on its capacity to recognise foreign- and self- molecules to survey the environment and detect anomalies or danger. Most evolved organisms have developed a sophisticated system of proteins capable of encountering, processing and binding antigens that subsequently will be presented to the cells that drive the immune response (Castro et al., 2015). Classically understood antigen presentation comprises short peptides that bind to MHC (Major Histocompatibility Complex) molecules that in turn will be co-recognised by different subsets of T cells via T cell receptors (TCRs) (Hennecke and Wiley, 2001; Wieczorek et al., 2017). The molecular mechanism of MHC-peptide-TCR assembly and its function in triggering immune responses have been extensively studied and represent one of the most critical arms of modern immunology (Kedzierska and Koutsakos, 2020). However, in the last few decades it has become evident that certain human cells express proteins that, although structurally related to MHCs, do not bind peptides but rather capture other non-peptidic molecules instead (Martin et al., 1987). These non-classical MHC-like proteins and their ligand antigens are recognised by specific subsets of αβ and γδ T cells and form a fundamental part of the human immune system (Blumberg et al., 1995, Russano et al., 2007). For instance, MR1 binds and presents small compounds such as vitamin B metabolites and CD1 proteins capture lipid antigens (Kjer-Nielsen et al., 2012, Layre et al., 2014). CD1, or Cluster of Differentiation 1, is a family of proteins that in humans includes five isoforms: CD1a, CD1b, CD1c, CD1d and CD1e (C. Y. Yu and Milstein, 1989). All five can bind lipid molecules, however CD1e lacks the transmembrane domain and is not known to directly participate in the immune responses via T cell recognition (Garcia-Alles et al., 2011). The other four CD1 proteins are expressed on the cell surface but differ in their expression pattern, the size and shape of their binding cleft and the intracellular processing pathways. CD1d is by far the most extensively investigated member of the group because it is the only one found in rodents, making its functional studies in vivo more feasible (Balk et al., 1989, Bradbury et al., 1990; Ichimiya et al., 1994). CD1a, CD1b and CD1c altogether belong to group 1 CD1 proteins and, while absent in rodents, possess known orthologs across many species of mammals (Chun et al., 1999, Dossa et al., 2014, Van Rhijn et al., 2006). CD1b and CD1c are expressed on a range of different immune cells and play a role in autoimmunity and in responses to pathogens such as Mycobacterium tuberculosis (Gras et al., 2016, Reijneveld et al., 2021, Shahine et al., 2017, Wun et al., 2018). The molecular details of T cell-mediated recognition of different CD1 proteins have been recently reviewed (Shahine et al., 2021). CD1a is highly expressed on Langerhans cells in human epidermis, where it binds lipid ligands and triggers T cell activation that participates in skin homeostasis, response to pathogens and autoimmune diseases. Since its discovery over thirty years ago, CD1a and the T cells that recognise it have been extensively studied in the context of the skin immunity (Cotton et al., 2021a, de Jong et al., 2014, Elias et al., 2003, Hunger et al., 2001, Martin et al., 1987; Yu et al., 2002). Recently, we solved the crystal structure of CD1a-γδTCR complex, showing for the first time how group 1 CD1 proteins can be recognised by autoreactive γδ T cells, opening a new interesting chapter in the CD1a biology (Wegrecki et al., 2022). Further, a new study has linked CD1a to the systemic inflammation in a transgenic mouse model (Hardman et al., 2022) and the expansion of CD1a-restricted T cells has been described in people with atopic dermatitis (Monnot et al., 2023), thus consolidating our focus on CD1a as an interesting molecule with therapeutic potential. Here we summarise our current understanding of the CD1a system with a special emphasis on the molecular mechanism underpinning the presentation of lipid antigens and the recognition of CD1a-lipid complexes by T cells.