Despite improvement of operating procedures and publication of safety guidelines, contamination is still observed in healthcare settings where antineoplastic drugs (ADs) are handled. Even after cleaning work areas, some residual contamination may still be present. Zero percent contamination is not a realistic goal, but the scientific community should set zero contamination as its main goal. The strategies to reach this objective may be traced based on the followings: (a) a wider number of drugs should be monitored; (b) safety equipment and devices must be available to the workers; (c) the likely source of widespread contamination in workplaces is the safety cabinet; (d) direct determination of the parent drug or its metabolite in urine is the recommended approach because it provides higher sensitivity and specificity; (e) reliable analytical methods are necessary to measure the extent of contamination; and (f) analytical methods intended to be applied for routine testing must be assessed through method validation studies. These studies rely on the determination of overall method performance parameters including uncertainty measurement. Our laboratory has developed and validated a number of analytical methods for the determination of several drugs in environmental and biological samples. Surveys were carried out in several hospitals, and there has been progressive, significant decrease in the number of positive samples, mostly due to the improvement of working procedures and safety measures.