The well-established increased cardiovascular risk that is a hallmark of chronic kidney disease (CKD) has directed research to metabolic changes that are typical of CKD. Epidemiological data point to derangements of mineral metabolism to be involved in this risk profile. Subsequently, newly discovered humoral factors - such as fibroblast growth factor (FGF)-23 - that are involved in mineral and vitamin D homeostasis turned out to be associated with clinical outcome, independently of the minerals they regulate. Additional proteins involved in FGF-23 signaling, such as Klotho, subsequently appeared to have FGF-23-independent effects as well. In this review, the discovery, mode of action, and clinical implications of these new factors are outlined.