Important challenges in understanding human genetic diseases include (i) identifying disease genes and (ii) obtaining mechanistic insights into disease etiology. Addressing these challenges is essential to understand disease pathogenesis and design intervention, and prevention strategies. Decades long research has identified disease genes associated with several human genetic diseases. Recent advances in building databases, integrating, and analyzing multiple large-scale datasets, especially in the field of network biology, have permitted elucidating properties of disease genes at systems level. In this chapter, we will discuss how disease and disease gene networks have shed light on the properties of different diseases, their shared genetic architecture and how different genes contribute to comorbidity. Furthermore, we discuss about the position of the disease genes in the protein interaction networks, their implications and how the lessons learnt by analyzing systems properties of disease genes are being exploited to prioritize novel disease candidates, and how these advances provide mechanistic insights into disease pathogenesis. We outline some important problems that need to be addressed to realize better diagnosis, prevention, and intervention. ©2013 Wiley-VCH Verlag GmbH & Co. KGaA.