The first cGMP-dependent protein kinase (PKG) modulators were described nearly 30 years ago and since then more than 200 compounds have been synthesized and tested, but only a small subset of these compounds has found widespread application. The aim of this review is to suggest a framework for evaluating and using PKG activators and inhibitors and to explore and interpret PKG signal transduction in cell culture-based model systems. Therefore, cross-reactivity of cGMP-analogs with other classes of cyclic nucleotide binding proteins, as well as the advantages and problems of newly designed PKG inhibitors, are discussed. Additional information and a search option are available at www.cyclic-nucleotides.org