The positive benefit-risk ratio of most drugs is decreasing in correlation to very old age, the extent of comorbidity, dementia, frailty and limited life expectancy (VOCODFLEX). First, we review the extent of inappropriate medication use and polypharmacy (IMUP) globally and highlight its negative medical, nursing, social and economic consequences. Second, we expose the main clinical/practical and perceptual obstacles that combine to create the negative vicious circle that eventually makes us feel frustrated and hopeless in treating VOCODFLEX in general, and in our 'war against IMUP' in particular. Third, we summarize the main international approaches/methods suggested and tried in different countries in an attempt to improve the ominous clinical and economic outcomes of IMUP; these include a variety of clinical, pharmacological, computer-assisted and educational programs. Lastly, we suggest a new comprehensive perception for providing good medical practice to VOCODFLEX in the 21st century. This includes new principles for research, education and clinical practice guidelines completely different from the 'single disease model' research and clinical rules we were raised upon and somehow 'fanatically' adopted in the 20th century. This new perception, based on palliative, geriatric and ethical principle, may provide fresh tools for treating VOCODFLEX in general and reducing IMUP in particular.