Background: Streptomyces coelicolor, a model organism of antibiotic producing bacteria, has one of the largest genomes of the bacterial kingdom, including 7825 predicted protein coding genes. A large number of these genes, nearly 34%, are functionally orphan (hypothetical proteins with unknown function). However, in gene expression time course data, many of these functionally orphan genes show interesting expression patterns. Results: In this paper, we analyzed all functionally orphan genes of Streptomyces coelicolor and identified a list of "high priority" orphans by combining gene expression analysis and additional phylogenetic information (i.e. the level of evolutionary conservation of each protein). Conclusions: The prioritized orphan genes are promising candidates to be examined experimentally in the lab for further characterization of their function. © 2011 Breitling et al; licensee BioMed Central Ltd.