Galectin-3 is a b-galactoside-binding protein that is involved in inflammation and cancer progression. In cancer, galectin-3 has been shown to induce proliferation of cancer cells, metastasis and increased resistance to apoptosis inducing treatments. The design of selective and potent inhibitors of human galectin-3 is necessary for use as potential therapeutics or as molecular probes. Traditionally, inhibitor design has been based on a galactose framework, as it is the natural substrate. Previous work from our group and others showed that saccharide-based small molecule inhibitors of galectins are effective against cancer progression. However, recent reports indicate that different galectins can play different roles in certain cancers, as exemplified by galectin-4, which can suppress cancer progression and metastasis in colon and pancreatic cancer models in stark contrast to galectin-3. As the leading candidates for galectin-3 inhibitors, such as thiodigalactosides and modified citrus pectin are largely non-selective, we have initiated the design of inhibitors based on an alternative talose-based framework that allows exploitation of additional interactions with the galectin-3 protein. Despite initial taloside-based inhibitors showing selectivity for galectin-4 and galectin-8 over galectin-3, we have utilized in silico docking and modelling approaches to design and optimize new galectin-3-specific, high affinity taloside based inhibitors that exploit the unique features of galectin-3 near its binding pocket. The elucidation of the crystal structure of galectin-3-inhibitor complexes confirms the binding mode predicted from in silico docking. Preliminary results indicate that the inhibitors are capable of inducing cytotoxicity in a variety of galectin-3-expressing cancer cells. Further work is being performed to confirm the mode of action in cells.