Immunotoxins combining antibody specificity with bacterial or plant toxins are limited by their strong immunogenicity and non-specific toxicity. Ribonucleases of the RNase A protein superfamily provide a solution to address these issues because they show potent antineoplastic activity on cell internalization but do not show appreciable immunogenicity or non-specific toxicity. Their therapeutic value is demonstrated by RNase derived from the frog (Rana pipiens), Onconase (ONC, Alfacell, Inc., New Jersey, USA), the first and only RNase being evaluated in clinical trials at present. Conjugation or fusion of RNases to tumor specific antibodies is a promising approach to further boost tumor cell killing of these compounds. This review focuses on 'targeted RNases/ImmunoRNases' as promising novel anticancer therapeutics.