Noninvasive or minimally invasive alternatives are proposed as substitutes for liver biopsy and include clinical indices, cross-sectional imaging, serum biomarkers, liver stiffness measurement, and portal pressure measurement. Most alternatives to liver biopsy assess one aspect of liver disease and translate this into a numeric score. Overlap between categories may limit applications. Liver biopsy provides information about numerous variables: tissue architectural changes; necroinflammatory injury; fibrotic stage; alterations of parenchyma and bile duct epithelium; accumulation of fat, copper, and iron; and molecular and genetic changes. Liver biopsy may identify multiple disease etiologies. A single numeric score cannot be a substitute for complete histologic assessment. However, within defined clinical contexts, noninvasive assessment is an attractive alternative for many patients given the ease, avoidance of risk from invasive procedures, and validated contribution to clinical management. Serum biomarkers and liver stiffness assessment may become indispensable in longitudinal studies and to document outcome of treatments. The accuracy of the more reliable techniques is typically around 80%. Neither liver biopsy nor any single alternative option represents an absolute assessment of liver disease. Biopsy and alternatives are not mutually exclusive options. Liver biopsy and the noninvasive alternatives require a clear understanding of significance and limitations of each investigation. This places a responsibility on the clinician to consider fully the results of any of the investigative options used within the diagnostic and prognostic context of each individual patient, and to choose critically the most appropriate investigations for the patient's needs.