In clinical practice, many patients with heart failure with reduced ejection fraction (HFrEF) are either not prescribed guideline-directed medical therapies for which they are eligible or are prescribed therapies at sub-target doses. The objective of this study was to examine the factors associated with not receiving guideline-directed medical therapies or receiving sub-target doses. We conducted a systematic review of articles published between January 2014 and May 2019 that described dosing patterns and factors associated with non-use and sub-target dosing of HFrEF therapies in clinical practice. Thirty-seven studies were included. The percentages of patients reaching target doses for angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, sacubitril/valsartan, beta-blockers, and mineralocorticoid receptor antagonists ranged from 4 to 55%, 11 to 87%, 4 to 60%, and 22 to 80%, respectively. Older age and worsening renal function were associated with non-use and sub-target dosing, lower body mass index was commonly associated with non-use, and hyperkalemia and hypotension were commonly associated with sub-target dosing. In conclusion, several common patient characteristics are associated with non-use and sub-target dosing of medical therapy for HFrEF. These high-risk groups are in particular need of further studies to improve implementation of available medications and to define the role of novel therapies.