Several complex diseases are caused by the malfunction of human metabolism, and deciphering the underlying molecular mechanisms can elucidate their aetiology. Systems biology is an integrative approach combining experimental and computational biology to identify and describe the molecular mechanisms of complex biological systems. Systems medicine has the potential to elucidate the onset and progression of complex metabolic diseases through the use of computational approaches. Advances in biotechnology have resulted in the provision of high-throughput data, which provide information about different metabolic processes. The systems medicine approach can utilize such data to reconstruct genome-scale metabolic models that can be used to study the function of specific enzymes and pathways in the context of the complete metabolic network. In this review, we outline the importance of genome-scale models in systems medicine and discuss how they may contribute towards the development of personalized medicine.