The glomerular filtration barrier separates blood from the urinary space. It is composed of 2 cell types: an outermost sheet of podocytes separated from the fenestrated endothelial cells by an intervening glomerular basement membrane. Crosstalk between intrinsic cell compartments of the glomerulus is essential for glomerular development and maintenance. Recent advances in mouse genetics make it possible to dissect the pathomechanisms of glomerular disease and function in vivo. Cre-loxP conditional gene targeting, siRNA in vivo and inducible gene targeting systems are all options readily available to the renal researcher. The development of numerous Cre-driver transgenic lines for the majority of cell lineages within the glomerulus allows precise control over genetic manipulation in specific cell types. An overview of available techiniques, together with a discussion of advantages and caveats will be provided. A number of examples of successful mouse models generated by conditional gene targeting within the glomerulus will be presented and include: the role of angiogenic signaling systems such as VEGF and angiopoietins, effects of stabilization of hypoxia inducible factors and the effect of genetic inhibition of mTor (the mammalian target of rapamycin).