Introduction: The only drug effective against the infection caused by Fasciola hepatica or F. gigantica is triclabendazole (TCBZ), recommended by the WHO and recently approved by the FDA. Here, we describe the evolution of TCBZ regimens and the emergence of TCBZ failure to Fasciola infection. Areas covered: The present review focuses on the evidence of TCBZ for the treatment of fascioliasis. For acute fascioliasis, there is a lack of studies to measure the presence of eggs of Fasciola in stool samples on the follow-up after initial TCBZ treatment. For chronic fascioliasis, WHO recommends a single oral dose of TCBZ 10 mg/kg whereas CDC recommends two doses of TCBZ 10 mg/kg 12 h apart. Incremental number of treatment failures have been documented worldwide. There are currently no therapeutic alternatives for the treatment of fascioliasis in humans. Expert opinion: Most cases of human fascioliasis are successfully treated with TCBZ, but some continue excreting eggs in the stools despite 1–2 standard of care regimens of TCBZ. A precise regimen is unclear for those patients who fail the initial treatment with TCBZ. Further clinical trials are needed to address the possible TCBZ emerging resistance.