A number of highly specific small molecule inhibitors of oncogenic tyrosine kinases have been developed and may potentially improve the treatment of different malignant diseases. However, it became rapidly evident that multiple resistance mechanisms compromise the successful clinical application of these inhibitors, particularly in advanced solid tumors. To develop efficient therapeutic strategies with small molecule inhibitors, one must understand the causes for treatment failure. Three different types of resistance to small molecule inhibitors of oncogenic tyrosine kinases have been observed. The malignant phenotype may be independent of the activity of the target kinase (target-independent resistance). Alternatively, overexpression or mutation of the target kinase can counteract the inhibition of oncogenic tyrosine kinases (target-dependent resistance). Finally, alterations of drug transporters or drug-metabolizing pathways may block the bioavailability of the tyrosine kinase inhibitors (drug-dependent resistance). This article reviews the current knowledge of clinical resistance to small molecule inhibitors approved for treatment of cancer patients.