Mitochondrial diseases are inherited disorders of oxidative phosphorylation that present with a multitude of clinical features in different combinations and with various inheritance patterns. To complicate the issue further, the clinical features of mitochondrial disorders overlap with common neurological and non-neurological diseases. This presents a diagnostic challenge: when is a rare mitochondrial disease responsible for a more ‘common or garden’ neurological presentation, and how often are neurologists missing them in routine clinical practice? Here, we briefly review some common clinical features associated with mitochondrial disease, and provide some clues as to how patients with these mitochondrial disorders might be identified. We discuss both ‘chameleons’—mitochondrial disorders that may look like something else, and ‘mimics’—other conditions that may clinically resemble mitochondrial disease. The diagnosis sometimes needs highly specialised tests, but the advent of ‘next generation’ sequencing will simplify the clinical approach over the next few years.