Lipid-lowering guidelines emphasize shared decision-making between clinicians and patients, resulting in patients anticipating the degree of response from diet or drug therapy. Challenging for physicians is understanding the sources of variability complicating their management decisions, which include non-adherence, genetic considerations, additional lipid parameters including lipoprotein (a) levels, and rare systemic responses limiting benefits that result in non-responsiveness to monoclonal antibody injection. In this narrative review, we focus on the variability of low-density lipoprotein cholesterol (LDL-C) response to guideline-directed interventions such as statins, ezetimibe, bile acid sequestrants, fibrates, proprotein/convertase subtilisin-kexin type 9 inhibitors, and LDL-C-lowering diets. We hypothesize that the variability in individual lipid responses is multifactorial. We provide an illustrative model with a check list that can be used to identify factors that may be present in the individual patient.