Nowadays, liquid chromatography (LC) has an established place among other analytical techniques. This separation technique is commonly used in pharmaceutical laboratories. LC method optimization is usually realized by a trialand- error method based on the knowledge of the chromatographic process. Therefore, LC method development is often time-consuming and involves intensive exploitation of equipment and a substantial consumption of chemicals. Over the last few years, the progress in computer program development has assisted chromatographers in method development also. The rational selection of optimized experimental conditions for the chromatographic separation of analytes can also be realized nowadays by means of specialized algorithms (especially applying those used in the commercially available DryLab and ChromSword software). The aim of the study is to present recent achievements associated with the optimization of chromatographic separations of drugs and related compounds realized in reversed-phase liquid chromatography (RP-LC) systems. Considering applications in pharmaceutical analysis, several examples are provided. Optimization based just on experimental chromatographic measurements and additionally employing the quantitative structure-retention relationships (QSRR) is discussed in view of the opportunity to obtain practically useful separation information.