Genomics has made enormous progress in the twelve years since the publication of the first draft human genome sequence, but it has not yet been translated into the clinic. Despite spiralling development costs, the number of new drug registrations is not increasing. One reason for this lies in the genetic complexity of disease. Most diseases involve dysregulation in pathways that involve many genes, and many (including most cancers) are themselves genetically heterogeneous. Systems biology involves the multi-level simulation of physiology, cell biology and biochemistry using complex computational techniques. We show here using case studies in cancer and HIV how such computational models, and particularly models based on individual patient data, can be used for drug design and development, and in the selection of the appropriate treatment for a given patient in the face of resistance mutations. If these techniques are to be adopted in routine clinical practice, clinicians will need better training in modern approaches to the integrated analysis of large-scale heterogeneous data and multi-scale models, while developers will need to provide much more usable tools. Investment in computational infrastructure is needed so that results can be returned on clinically relevant timescales and data warehouses designed with data protection as well as accessibility in mind.