The appropriate diagnosis and subtyping of cardiac amyloidosis (CA) is frequently missed or delayed due to its vague presentation, clinical overlapping, and diagnostic pitfalls. Recent developments in both invasive and non-invasive diagnostic techniques have significantly changed the diagnostic approach of CA. With the present review, we aim to summarize the current diagnostic approach of CA and to underline the indications of tissue biopsy, either surrogate site or myocardial. The most important factor for timely diagnosis is increased clinical suspicion, especially in certain clinical scenarios. Appropriate imaging with echocardiography or cardiac magnetic resonance (CMR) can provide significant evidence for the diagnosis of CA. Importantly, all patients should undergo monoclonal proteins assessment, with these results significantly determining the steps to follow. A negative monoclonal protein assessment will lead to a non-invasive algorithm which, in combination with positive cardiac scintigraphy, can establish the diagnosis of ATTR-CA. The latter is the only clinical scenario in which the diagnosis can be established without the need of biopsy. However, if the imaging results are negative but the clinical suspicion remains high, a myocardial biopsy should be performed. In the case of the presence of monoclonal protein, an invasive algorithm follows, first by surrogate site sampling and then by myocardial biopsy if the results are inconclusive or prompt diagnosis is needed. The role of endomyocardial biopsy, even though limited by current advances in other techniques, is highly valuable in selected patients and is the only method to reliably establish a diagnosis in challenging cases.