The noncanonical class IV SLRPs chondroadherin, nyctalopin, and tsukushi share a common evolutionary origin, and these SLRPs provide mechanical strength, adhesion, and support to the cellular microenvironment that shapes tissue-specific function. At a molecular level, characteristic features of class IV SLRPs include the lack of ear repeats, and they present a protein core molecule with eleven leucine-rich repeats attached to the N-terminus. Nyctalopin is the only SLRP member with a glycosylphosphatidylinositol-anchored side chain attached to the C-terminus and linked to the X chromosome. Mutations in nyctalopin have been reported to cause congenital stationary night blindness (CSNB1). Chondroadherin is a cartilage growth plate-specific SLRP that is distinct from other members as it presents a double disulfide loop close to its C-terminus. Tsukushi has important regulatory functions in modulating BMP and Wnt signaling pathways in various types of tissue. Accordingly, this chapter aims to highlight the importance of Class IV SLRPs in regulating tissue-specific functions, particularly in the tissue types where they are predominantly expressed.