There is wide variability in the use and adoption of recommendations generated by computerized clinical decision support systems (CDSSs) despite the benefits they may bring to clinical practice. We conducted a systematic review to explore the barriers to, and facilitators of, CDSS uptake by physicians to guide prescribing decisions. We identified 58 studies by searching electronic databases (1990-2007). Factors impacting on CDSS use included: the availability of hardware, technical support and training; integration of the system into workflows; and the relevance and timeliness of the clinical messages. Further, systems that were endorsed by colleagues, minimized perceived threats to professional autonomy, and did not compromise doctor-patient interactions were accepted by users. Despite advances in technology and CDSS sophistication, most factors were consistently reported over time and across ambulatory and institutional settings. Such factors must be addressed when deploying CDSSs so that improvements in uptake, practice and patient outcomes may be achieved.