Homology modeling is based on the observation that related protein sequences adopt similar three-dimensional structures. Hence, a homology model of a protein can be derived using related protein structure(s) as modeling template(s). A key step in this approach is the establishment of correspondence between residues of the protein to be modeled and those of modeling template(s). This step, often referred to as sequence-structure alignment, is one of the major determinants of the accuracy of a homology model. This chapter gives an overview of methods for deriving sequence-structure alignments and discusses recent methodological developments leading to improved performance. However, no method is perfect. How to find alignment regions that may have errors and how to make improvements? This is another focus of this chapter. Finally, the chapter provides a practical guidance of how to get the most of the available tools in maximizing the accuracy of sequence-structure alignments.