Poor long-term adherence and persistence to drug therapy is universally recognized as one of the major clinical issues in the management of chronic diseases, and patients with renal diseases are also concerned by this important phenomenon. Chronic kidney disease (CKD) patients belong to the group of subjects with one of the highest burdens of daily pill intake with up to >20 pills per day depending on the severity of their disease. The purpose of the present review is to discuss the difficulties encountered by nephrologists in diagnosing and managing poor adherence and persistence in CKD patients including in patients receiving maintenance dialysis. Our review will also attempt to provide some clues and new perspectives on how drug adherence could actually be addressed and possibly improved. Working on drug adherence may look like a long and tedious path, but physicians and healthcare providers should always be aware that drug adherence is in general much lower than what they may think and that there are many ways to improve and support drug adherence and persistence so that renal patients obtain the full benefits of their treatments. The goal of the present review was to re-emphasize the crucial role of drug adherence in the management of CKD patients at any stage of the disease including on maintenance haemodialysis. Poor adherence should be taken into consideration in all clinical situations in which targets are not reached despite substantial efforts to prescribe the most adequate therapies. Because of the complexity of treatment and the high pill burden, CKD patients are at very high risk of poor adherence and should definitively be supported in their efforts to maintain a good persistence. Physicians and all other healthcare professionals should be aware of the different strategies available to help their patients and should join their efforts to alleviate the barriers to good adherence by improving the communication, reducing the pill burden and if possible by monitoring drug adherence occasionally when there is suspicion of poor adherence.