The receptor domains of Toll-like receptors (TLRs) are characterized by a solenoid-like structure composed of tandem repeats of α/β units known as Leucine Rich Repeats (LRRs). LRR proteins form large paralogous families, with nearly 400 in the human genome alone, all sharing similar semi-regular solenoid-like structures. Despite this structural similarity, they exhibit remarkable diversity in binding specificity. For TLR receptors, this includes a range of pathogen-associated molecular patterns (PAMPs), while other LRR proteins bind an extensive array of ligands, including proteins, DNA, RNA, and small molecules. The LRR domains contain repeats that have similar, yet not identical, 3D structures and patterns of conserved residues. Through in-depth analysis of sequence and structural conservation in individual repeats of human TLRs, we demonstrate that even subtle variations between these repeats alter the local solenoid structure, leading to significant functional changes. Variations in repeat length and defining patterns result in local changes in curvature and the emergence of structural features such as loops, cavities, or specific interaction interfaces. Understanding how divergence in LRR repeats influences their functional roles can provide deeper insights into their binding mechanisms, including interactions with unknown ligands, both in humans and across the diverse phylogenetic spectrum of animals that rely on their TLR repertoires for immune activation.