Somatic cells have been reprogrammed into pluripotent stem cells by introducing a combination of several transcription factors, such as Oct3/4, Sox2, Klf4 and c-Myc. Induced pluripotent stem (iPS) cells from a patient's somatic cells could be a useful source for drug discovery and cell transplantation therapies. However, most human iPS cells are made by viral vectors, such as retrovirus and lentivirus, which integrate the reprogramming factors into the host genomes and may increase the risk of tumour formation. Several non-integration methods have been reported to overcome the safety concern associated with the generation of iPS cells, such as transient expression of the reprogramming factors using adenovirus vectors or plasmids, and direct delivery of reprogramming proteins. Although these transient expression methods could avoid genomic alteration of iPS cells, they are inefficient. Several studies of gene expression, epigenetic modification and differentiation revealed the insufficient reprogramming of iPS cells, thus suggesting the need for improvement of the reprogramming procedure not only in quantity but also in quality. This report will summarize the current knowledge of iPS generation and discuss future reprogramming methods for medical application.