The complexity of stem cell niches poses a tremendous challenge to understanding mechanisms of extrinsic regulation of stem cell fate. In order to better understand niche signaling and its effect on stem cell fate choices, in vitro systems are being engineered which recapitulate, in a simplistic but increasingly sophisticated manner, native stem cell niches. New technologies or new combinations of existing technologies allow more systematic ways to probe niche signaling in high-throughput. Systems biology approaches in experimental design, data acquisition and analysis will be necessary to tackle the challenges that lie ahead.