Leucine-rich repeat (LRR)-containing proteins are present in over 4700 proteins from viruses to eukaryotes. Many LRR proteins are involved in protein, ligand interactions; these include plant immune response and the mammalian innate immune response. This review describes the present status of our understanding of their structures, functions, evolution and interactions with ligands. Most LRRs are 20 to 30 amino acids long and the repeat number ranges from 2 to 52. The LRR proteins have been divided into seven classes. One group of proteins has LRRs from more than one of the seven classes. The subfamily of small leucine-rich repeat proteoglycans and its related proteins including FLRT, ECM2, oligodendrocyte-myelin and glycoprotein, and Slit have two types of LRRs (S and T). These S and T LRRs are ordered into two super-motifs - STT and ST. A probable pattern of evolution of the SLRP and its related proteins was proposed based on the super-motifs. The known structures of the LRR proteins have revealed that the LRR domains fold into an arc shape with a parallel β-sheet on the concave face and with various secondary structures including the α-helix, 3 10-helix, and polyproline II helix on the convex face. Four geometric parameters, the radius (R) of the LRR arc, its mean rotation angle (φ), the tilt angle of β-strand direction per turn (θt), and the mean twist angle of b-sheets (|τ|) were estimated. These parameters well characterize all the LRR arcs. Most of the known LRR structures have a cap, which shields the hydrophobic core of the N-terminal LRR or the C-terminal LRR. The concave surfaces of the arcs frequently interact with ligands. Interactions on the concave surfaces induce an increase in R and θt. There is growing evidence of striking similarities between the molecular organization of both animal and plant systems for non-self recognition and antimicrobial defense.