Fibronectin Leucine-rich Repeat Transmembrane (FLRT 1–3) proteins are a family of broadly expressed single-spanning transmembrane receptors that play key roles in development. Their extracellular domains mediate homotypic cell-cell adhesion and heterotypic protein interactions with other receptors to regulate cell adhesion and guidance. These in trans FLRT interactions determine the formation of signaling complexes of varying complexity and function. Whether FLRTs also interact at the surface of the same cell, in cis, remains unknown. Here, molecular dynamics simulations reveal two dimerization motifs in the FLRT2 transmembrane helix. Single particle tracking experiments show that these Small-X3-Small motifs synergize with a third dimerization motif encoded in the extracellular domain to permit the cis association and co-diffusion patterns of FLRT2 receptors on cells. These results may point to a competitive switching mechanism between in cis and in trans interactions, which suggests that homotypic FLRT interaction mirrors the functionalities of classic adhesion molecules. Display omitted •Identification of in cis interaction sites of FLRT2 receptor•Characterization of the transmembrane domain interactions using MD simulations•SMT experiments reveal a bipartite interaction mechanism involving the ectodomain FLRTs are a family of broadly expressed receptors with key roles in neural development controlling the formation of signaling complexes in trans. Using a combination of molecular dynamics simulations and single molecule tracking experiments, Jackson et al. present structural insights into the in cis dimerization of FLRT2 receptors.