Cells require an internal architecture that supports tissue integrity and allows flexibility in development and repair. To this end they possess various protein families that contribute to accurate relative positioning and dynamics of different cytoskeletal networks and organelles. One large protein family that participates in the structural organization of cells and tissues is the spectrin repeat (SR) family. The spectrin repeat is a triple helical bundle of about 106 amino acids. In this characteristic structure, three alpha-helices are separated by two loops to form a coiled coil (Pasqual et al., 1997). Spectrin repeats are utilized to form flexible rods of variable length. The rod separates distinct functional domains of SR proteins. In the classical family members these comprise a calponinhomologous actin-binding domain in the N-terminus and a variable C-terminal domain that usually interacts with membrane lipids or membrane protein complexes. The classical SR family members are spectrins, α-actinins and dystrophins and their structure and functions are comprehensively covered in several recent reviews (Blake et al., 2001; Brakebusch and Fässler, 2003; Broderick and Winder, 2002; Djinovic-Carugo et al., 2002; Knust 2000). This chapter concentrates on the emerging new subfamilies, spectraplakins and nesprins, comprising giant cytoplasmic and nuclear proteins encoded by very large genes that are subject to complex alternative splicing (Röper et al., 2002; Zhang et al., 2001, 2002). We will review the structure and predicted isoforms of these proteins and evaluate what is known about spectraplakin and nesprin functions based on cell culture studies and on phenotypes of mutated model organisms.