Nearly 20 years after its first description, gene targeting and generation of transgenic mice by homologous recombination in embryonic stem cells still are cutting edge tools for the postgenomic era. Understanding the function of the large number of genes encoding extracellular matrix proteins and their cellular receptors appears a daunting task that can very much profit from a genetic approach. The generation of new mutant alleles remains essential to define the different biochemical properties of such proteins. While in the past, gene targeting represented a complex procedure, restricted to few laboratories, recent breakthroughs, such as the publication of the mouse genome sequence and the perfection of recombineering techniques in bacteria, made generation of transgenic mice faster and easier. This chapter will thus focus on the recent advances in gene-targeting technology with a special eye on the study of genes involved in cell adhesion and migration.