RNAi technology is now a well-established and widely employed research technique that has been adopted by many researchers for use in large-scale screening campaigns. Here, we offer our experience of genome-wide siRNA screening from the perspective of a facility providing screening as a service to a wide range of researchers with diverse interests and approaches. We have experienced the emotional rollercoaster of screening from the exuberant early promise of a screen, the messy reality of the data through to the recognition of screen data as a potential information goldmine. Here, we use some of the questions we most frequently encounter to highlight the initial concerns of many researchers embarking on a siRNA screen and conclude that an informed view of what can be reasonably expected from a screen is essential to the most effective implementation of the technology. Along the way, we suggest that for this area of research at least, either centralization of the resources or close and open collaboration between interested parties offers distinct advantages.