Development of an efficient, sensitive and robust HPLC method for pharmaceutical analysis could be very challenging due to the sample complexity and stringent regulatory requirement. Here we reported the systematic strategies and processes to develop HPLC methods for pharmaceutical applications. These include: 1) Define separation goal; 2) Collect sample information; 3) Search for similar methods; 4) Design initial experiment; 5) Develop a preliminary method; 6) Screen HPLC columns to identify the most suitable stationary phase; 7) Optimize the HPLC parameters on the most suitable stationary phase; 8) Identify an alternate column; 9) Verify method validation characteristics; and 10) Assess column lifetime. An example was used to demonstrate successful method development by following the above approaches. We believe that systematic approach using ChromSword� and LC-SpiderlingTM column switcher significantly improves the efficiency of HPLC method development, and ChromSword� simulation improves the possibility of developing a more efficient, sensitive, and robust method.