Disclosed are systems biology-based methods for repositioning known pharmaceutical compounds to new indications, through the identification of network-based signatures. In particular, the invention provides new and useful methods for selecting drugs or combinations of drugs (and preferably previously-approved drugs) for use in new therapeutic indications. Also disclosed are methods for identifying anti-breast tumor initiating cell (TIC)-based therapeutics from within populations of target compounds. In illustrative embodiments, the invention provides methods and computer programs for the repositioning of FDA-approved pharmaceutical compounds to new indications using network-based signature analysis coupled with conventional in vitro and in vivo testing of identified drug candidates. The invention also allows identification of drugs or drug combinations for treating unmet medical needs including, for example, “orphan” diseases.