Steadily, cancer is becoming the first cause of mortality, with over 9 million deaths estimated in 2018. Increasing evidence supports a direct association between obesity, type 2 diabetes mellitus (T2DM) and cancer, with a higher risk of cancer mortality especially for some of the most common malignancies, such as breast, colon, and rectal cancers. So far, several mechanisms underlying the cancer-diabetes relationship have been investigated revealing dysregulations of the insulin-insulin-like growth factor (IGF) system as the most important paradigm. Other molecular mechanisms that seem to play a role in the association cancer-T2DM consist of alteration of the signaling pathways activated by inflammatory cytokines, adipocytokines or adhesion molecules. The overall aim of this review is to provide an overview of the molecular mechanisms linking obesity, T2DM and cancer, as related to the receptors and signaling pathways involved in these associations.