A method of recanalizing a chronic total occlusion (CTO) is disclosed. A catheter with a guidewire slidingly received therein is positioned proximally adjacent to the CTO. An occlusion weakening therapy effective to quickly soften and/or loosen the CTO is delivered to the CTO via the catheter. The occlusion weakening therapy includes at least one enzyme and a chelating agent which are selectively deliverable either together or separately depending on the type of material encountered by the guidewire. According to various methods, the enzyme(s) may be delivered if tissue is encountered, the chelating agent may be delivered if calcification is encountered, and both enzyme(s) and chelating agent(s) may be delivered if a fibrous cap is encountered. The distal end of the guidewire may be advanced into the CTO shortly after delivery of the occlusion weakening therapy and is manipulated through the CTO until the guidewire successfully crosses the CTO.