Abstract MicroRNA and other short or long non-codingRNAs alterations are involved in the initiation, progression and metastases of human breast cancer. The main molecular alterations are represented by variations in gene expression, usually mild and with consequences for a vast number of target protein coding genes. The causes of the widespread differential expression of non-codingRNAs in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the processing machinery. MicroRNA and other short or long non-codingRNAs expression profiling of human tumors has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify non-codingRNAs that may represent downstream targets of activated oncogenic pathways or that are targeting protein coding genes involved in breast cancer. Recent studies proved that miRNAs and non-coding ultraconserved genes are main candidates for the elusive class of cancer predisposing genes and that other types of non-codingRNAs participate in the genetic puzzle giving rise to the breast malignant phenotype. These discoveries could be exploited for the development of useful markers for diagnosis and prognosis, as well as for the development of new RNA-based cancer therapies. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr MS1-1.