Platelets are highly responsive to signals from their environment. The sensing and processing of some of these stimuli are mediated by G-protein signal transduction cascades. It is well established that proteins involved in signal transduction may be targets for naturally occurring mutations resulting in human diseases. The best-studied molecules in platelets in relation to disease are the G-protein coupled receptors being the most platelet-specific. Many of the other signal transduction genes are often not only present in platelets but also in other tissues. Therefore, the clinical phenotype of signaling defects in platelets, apart from the membrane receptor defects, is seldom isolated to a hemostatic phenotype. Moreover, as platelets are easily accessible cells, and one of the best-studied models regarding signaling, platelets are easily applicable to investigate defects in ubiquitously expressed genes. Apart from a discussion on classical thrombopathies, this review will also deal with the less commonly known relation between platelet signaling defects and disorders with a broader clinical phenotype.