The tribbles family of genes encodes pseudokinase proteins that are highly conserved in evolution. Instead of direct phosphorylation of target proteins, tribbles act as adaptors in signaling pathways for important cellular processes. These include mitogen-activated protein kinase kinase (MAPKK), CCAAT/enhancer-binding protein (C/EBP), activating transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP). Trib1 and Trib2 have been identified as myeloid oncogenes, and both may be involved in human leukemia. Tribbles proteins are also involved in a series of non-neoplastic disorders including metabolic and neurological diseases. The RAS/mitogen-activated protein kinase (MAPK) pathway molecules (in particular MAPK/ERK kinase 1 (MEK1) and C/EBP transcription factors) include tribbles-binding proteins that are involved in leukemogenesis, and the role of Trib1 as a linker between MAPK signaling and C/EBP degradation is proposed. Although the molecular function of tribbles is still under investigation, the research on tribbles in cellular processes, homeostasis of organisms and human diseases will provide valuable information for therapy of cancer as well as non-neoplastic disorders. (Cancer Sci 2011; 102: 1115–1122)