The scientific considerations surrounding the estimation of a minimally clinically important difference (MCID) are a myriad and challenging. There are a considerable number of hurdles to overcome. The good news is that there are solutions to virtually every one of the scientific hurdles. This paper intends to set out the issues, identify the challenges, and offer solutions so that the state of the science may move forward. The ultimate outcome of the paper may not be to provide a definitive answer for estimating the MCID in every situation, but it should provide a starting point and advice for a process or set of guidelines that may be followed toward achieving this goal. The paper begins with a brief synthesis of the literature and state of the science at the time of publication. The relationship between the process for determining MCIDs for other endpoints, such as tumor response or complete blood culture (CBC) variables, versus toxicity and QOL-related variables is described. The ultimate lessons to be learned from this exercise are: 1. There are many methods available to ascertaining an MCID. None are perfect, but all are useful. 2. All methods converge to similar answers. Supplementary information may refine answers from one or more of the methods. 3. Clinical opinion and patient subjective response should trump statistical theory. 4. A process of MCID estimation involving all approaches to produce a potential range with sensitivity analyses is the optimal solution to producing an MCID based on the most complete knowledge possible.