This chapter introduces a list of clinical presentations seen in a genetics clinic or on the ward such as ambiguous genitalia including sex reversal, anterior segment eye malformations, ataxic adult, broad thumbs, cataract, cerebral palsy, cleft lip and palate, coloboma, congenital heart disease, developmental regression, dysmorphic child, dystonia, ear anomalies, floppy infant, fractures, holoprosencephaly, hydrocephalus, hypermobile joints, large fontanelle, limb reduction defect, lumps and bumps, microcephaly, nasal anomalies, nystagmus, overgrowth, post-axial polydactyly, retinal dysplasia, scalp defects, and more. The chapter outlines a practical clinical approach with relevant investigations to help to achieve an accurate genetic diagnosis, together with genetic advice, and a list of support groups.