Antifungal stewardship programs have been developed to make antifungal use as good as possible. The most important and difficult issues of these program measures are therapeutic drug monitoring (TDM) and drug-drug interactions. TDM of antifungal drugs should be considered when there is an unpredictable drug dose-exposure relationship, a narrow therapeutic range and acceptable safety and efficacy concentration ranges defined. It is recommended for itraconazole, voriconazole, posaconazole and flucytosine in clinical practice. The case for TDM of fluconazole may be beneficial in special circumstances. For isavuconazole, there are insufficient data to support the routine use of TDM. Amphotericin B and echinocandins do not meet the criteria for TDM. Antifungal drugs are involved in many important drug-drug interactions at a high complexity and their management is difficult. Inhibition or induction of cytochrome P450 and P-glycoprotein enzyme systems by azoles is responsible for most drug interactions. There are also interactions that alter the bio-availability of itraconazole and posaconazole. The amphotericin B formulations interact with other drugs primarily by reducing their renal elimination. Echinocandins display a lower potential for drug-drug interactions. The individual approach is the cornerstone in the management of antifungal therapy. Several factors play a role in antifungal therapy response such as the host factors including underlying disease and/or immune status, fungal factors including primary drug resistance or development of resistance under therapy, and drug-related factors (i.e., pharmacokinetics and pharmacodynamics, toxicities, drug-drug interactions, low drug concentration at the site of infection). The patients who do not respond to primary antifungal therapy should be carefully reviewed for these factors.