Azoospermia is defined as the absence of spermatozoa in the ejaculate following centrifugation and subsequent microscopy of the specimen on two separate semen analyses. However, this definition in semen analysis is descriptive in nature and does not foretell its etiology, nor does this examination allow differential diagnosis in its evaluation. Thus, a critical initial step for a reproductive specialist is to ascertain whether the condition is attributable to obstructive azoospermia (OA) or nonobstructive azoospermia (NOA). The etiological factors contributing to OA and NOA are diverse and include congenital, genetic, physiological, surgical, inflammatory, and environmental factors. Identifying the specific type of azoospermia informs the choice of intervention and has implications for the prognosis and potential for fertility restoration. This chapter aims to present the key points with a clinical focus, offering a guide to essential diagnostic algorithms and options while pointing to additional pertinent literature for further exploration. NOA has been demonstrated to be distinguished from OA in most cases based on a detailed history, clinical examination, semen analysis, hormonal assessment, imaging, and genetic testing. Besides, genetic counseling of the couple is vital in special cases as male infertility due to NOA can stem from various genetic and nongenetic factors, including genetic counseling for NOA cases regarding the risk for malignancy, and genetic testing in selected men with specific sperm defects. In addition, the chapter discussed the available biochemical predictive markers for OA vs. NOA differentiation, the role of testicular histopathology, and the role of the diagnostic testicular biopsy. It was concluded that understanding the nuances and underlying mechanisms of both OA and NOA is paramount to developing more effective treatments and patient care protocols. The impact of both accurate diagnosis and treatment strategies is significant for NOA patients. Therefore, multifaceted, tailored diagnostic and therapeutic approaches are needed to improve their outcomes and success rates, requiring a precise diagnostic algorithm to determine the optimal therapeutic approaches and better-informed decision-making regarding different treatment options.